oajost: Vol. 6
Review Article
Nuclear Receptor Research
Vol. 6 (2019), Article ID 101447, 17 pages
doi:10.32527/2019/101447

Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors As a First Step in Protection from Xenobiotics

William S. Baldwin

Clemson University, Biological Sciences/Environmental Toxicology, 132 Long Hall, Clemson, SC 29634, USA

Received 20 November 2019; Accepted 2 October 2019

Editors: Manuel Vazquez Carrera and Pallavi R. Devchand

This article is part of a thematic issue titled “Lipid and Xenobiotic Signaling at the Nucleus
Lead Guest Editor: Pallavi R. Devchand
Guest Editors: Manuel Vazquez Carrera and Simon A. Hirota

Copyright © 2019 William S. Baldwin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

This mini-review examines the crucial importance of transcription factors as a first line of defense in the detoxication of xenobiotics. Key transcription factors that recognize xenobiotics or xenobiotic-induced stress such as reactive oxygen species (ROS), include AhR, PXR, CAR, MTF, Nrf2, NF-κB, and AP-1. These transcription factors constitute a significant portion of the pathways induced by toxicants as they regulate phase I-III detoxication enzymes and transporters as well as other protective proteins such as heat shock proteins, chaperones, and anti-oxidants. Because they are often the first line of defense and induce phase I-III metabolism, could these transcription factors be considered the phase 0 of xenobiotic response?

1. Introduction

The term phase I and phase II detoxication have been a part of the lexicon of the toxicology vocabulary since first coined by R.T. Williams in 1959 [1]. Phase I and II enzymes include the cytochrome P450s (CYPs), flavin-containing mono-oxygenases (FMOs), peroxidases, dismutases, and conjugases [glutathione S-transferase (GST), uridine diphospho-glucuronosyltransferases (UDPGT; UGT), and sulfotransferases (SULTs)] that hydroxylate, oxidize, reduce, desulfurize, epoxidate, and conjugate xenobiotics [2]. Phase I refers to the early oxidative metabolism of the xenobiotic, and phase II typically refers to conjugation but potentially to a second oxidative reaction such as de-epoxidation by epoxide hydrolase [3].

Later the discovery of xenobiotic transporters led to the term phase III and refers to proteins that eliminate xenobiotics from cells through membrane transport pumps [4]. Phase III transporters include key members of ATP-binding cassette (ABC) transporters primarily in groups ABCB and ABCC such as multidrug resistance associated protein 2 (MRP2), multidrug resistance protein (MDR1), and bile salt export pump (BSEP) [5-8] (Figure 1). Additional phase III transporters can also be found in groups such as ABCG (ABCG2; breast cancer resistance protein)[9]. Phase III transport can occur first, prior to transcription factor activation or phase I metabolism, as some xenobiotics are pumped out shortly after entering the cell by transporters such as MDR1 (also known as P-glycoprotein (PGP)). Therefore, phase III has been recently referred to as “phase 0 transport” because these transporters eliminate chemicals from the cell without prior phase I and II metabolism [10,11]. However, for clarity and recognition of “transport”, I propose that phase III be used whether or not metabolism occurs prior to membrane transport. Similarly, conjugation of xenobiotics (phase II) can also occur prior to phase I metabolism if the proper leaving group is available and yet conjugation is still called phase II [12-14].

F1
Figure 1: Phase 0 response to xenobiotics is activation of a transcriptional response by xenobiotic responsive transcription factors. Phase I-III detoxication is well documented and relatively well defined as oxidative metabolism, conjugation, and transport, respectively. Phase 0 xenobiotic response is defined as the transcriptional response of and initial acclimation of the cell to xenobiotics leading to increased phase I-III detoxication through gene regulation. R/TF = receptor/transcription factor.

Most of these phase I-III detoxification enzymes and transporters are inducible and elegantly regulated by a suite of transcription factors. We often refer to specific pathways in transcriptomics based on the transcription factor activated. Thus, given that transcription factors are often our first responders following chemical exposure, they could be considered our first phase of detoxication. However, the term phase I is already taken and well established in the literature. Therefore, transcription factors that initiate our molecular response to chemical intrusion and help individuals acclimate to xenobiotic insults be identified as “phase 0”, “phase 0 detoxication” or “phase 0 xenobiotic response” because these transcription factors act as the initial response that increases phase I-III metabolism (Figure 1).

1.1. Xenobiotic-responsive transcription factors

Transcription factors are any number of proteins that can help initiate or regulate transcription by binding DNA at specific promoter or enhancer sites [15]. The transcription factors crucial in toxicology can respond directly to xenobiotic exposure or respond to adverse metabolites or reactions caused by the chemicals such as increased ROS or perturbations in mitochondrial viability [16,17]. The list of transcription factors presented below is not exhaustive, but includes the most prominent transcription factors in acclimating to chemical stress.

Transcription factors typically perturbed by endo- or xenobiotic-mediated stress are trans-acting elements that can be activated by ROS, hormones, xenobiotics or any number of extracellular stress signals. In turn, the transcription factor activates transcription by binding to DNA at specific cis-elements (i.e. response elements; consensus sequences) sometimes called a Xenobiotic Response Element (XRE) when dealing with the response element is unique to a xenobiotic responsive transcription factor. There are several groups of transcription factors often classified based on the type of DNA binding motif that they contain such as zinc fingers (nuclear receptors), basic leucine zippers (bZIP), or basic helix-loop-helix (bHLH). An example is the bHLH group of transcription factors containing a basic region adjacent to a helix-loop-helix (HLH) domain [15]. HLH members include the aryl hydrocarbon receptor (AhR), a key transcription factor in toxicology [18].

1.1.1. AhR

The aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is a bHLH transcription factor in the Per-Arnt-Sim (PAS) family. It is an established xenobiotic receptor, as it is bound and activated by polycyclic aromatic hydrocarbons (PAHs), dioxins, and other coplanar aromatic compounds. It has additional functions based on the phenotype of untreated AhR-null mice, which include roles in the immune system, cardiac hypertrophy, cardiac development, hepatic growth, and oocyte development [19-23]. Cardiac toxicity is common in animals exposed to TCDD and other AhR agonists during development [24,25] and recent work shows mice treated with AhR agonists have a propensity towards obesity [26] and non-alcoholic fatty liver disease [27,28]. AhR is also involved in regulating tryptophan metabolism through the kynurenine pathway [29].

The AhR binds to a number of xenobiotics such as the halogenated aromatic hydrocarbons (HAHs), (i.e the dibenzo-p-dioxins, dibenzofurans, and polychlorinated biphenyls (PCBs)), and the polycyclic aromatic hydrocarbons (i.e. pyrene, 3-methylcholanthrene, benzo[a]pyrene) [30]. HAHs have higher affinities for the AhR than PAHs and this difference is strongly associated with toxicity [31,32]. It is assumed that the toxicity of HAHs and PAHs is due to the inappropriate expression of specific genes induced by AhR.

Following ligand activation, the AhR translocates to the nucleus, and mediates the transcription of a number of genes. Many of the proteins induced by AhR activation are detoxication enzymes and include CYP1A, CYP1B, NADPH:quinone oxidoreductase 1, and UDP-glucuronosyltransferase 1 [32-34] of which several are necessary for the metabolism of the xenobiotic and protection from its adverse effects. There is also data implicating AhR activity in the down-regulation of the estrogen receptor, glucocorticoid receptor, epidermal growth factor receptor, and CYP2C11 in mammals [35,36].

Activation of AhR in the cytosol displaces it from heat shock proteins (HSP90), HSP23 and the immunophilin chaperone Ara9 (also known as XAP2) [29,37]. This allows for translocation to the nucleus and association with the aryl hydrocarbon receptor nuclear translocator (ARNT). The AhR/ARNT complex binds to the xenobiotic response element (XRE, also known as the dioxin responsive element, DRE) and in turn activates basal transcription factors, the transcription of CYP1A, and other target genes (Figure 2). In addition, ligand binding to AhR also releases proto-oncogene tyrosine kinase (SRC), which is a tyrosine kinase that phosphorylates and activates the ERK1/2 pathway. SRC can also phosphorylate AhR, increasing nuclear translocation [38].

F2
Figure 2: The AhR is activated by ligands such as dioxin. Ligand activation induces the release of HSP90 and Ara9 and allows for translocation of the AhR into the nucleus. In the nucleus, the AhR binds ARNT and this complex binds the xenobiotic response element (XRE) and regulates transcription of CYP1A and other detoxification genes.

Interestingly, reported cardiotoxicity mediated by benzo(a)pyrene is significantly reduced in zebrafish lacking AhR activity and in turn Cyp1a induction; however, this is not true for all PAHs tested [39]. 2,3,7,8-tetrachlorodibenzo-p-dioxin's (TCDD) teratogenicity is significantly ameliorated in AhR-null mice demonstrating a role for the AhR and its transcriptional response in mediatiating toxicity [40,41]. Furthermore, a poor response to AhR agonists is associated with tolerance to dioxin and dioxin-like chemicals [18,42,43]. For example, Fundulus heteroclitus resistant to PAHs, polychlorinated biphenyls, and dioxins have been found in New Bedford Harbor, MA, Newark Bay, NJ, and the Elizabeth River, VA, and each of these populations demonstrate weak induction of CYP1A following chemical exposures primarily due to mutant AhRs [43-49].

1.1.2. Nuclear receptors (PXR, CAR, HR96)

The nuclear receptor superfamily contains several transcription factors of which most are activated by small lipophilic ligands such as steroids, bile acids, bilirubin, fatty acids, heme, and xenobiotics [50-52]. Several nuclear receptors have a role in protecting individuals from the build-up of toxic endobiotics, including farnesoid X-receptor (FXR) liver X-receptor (LXR), and the peroxisome proliferator activated receptors (PPARs); however, their role in xenobiotic metabolism and elimination is limited [53-62]. We will not consider these nuclear receptors for this review but it should be noted that they are crucial in the detoxication of endobiotics including bile acids, bilirubin, fatty acids, and oxysterols [53, 58, 60, 63-65].

PPARs, Vitamin D receptor (VDR), GR, and the retinoid receptors; RAR and RXR, are considered new targets for endocrine disruption by xenobiotics, in addition to the traditional endocrine targets such as estrogen receptors, thyroid hormone receptors and androgen receptors (all within the nuclear receptor family) [58]. In addition, new nuclear receptors have been discovered recently in several invertebrate species including some within the xeno-sensing clade [51, 66-68]. Of these “non-toxicology” nuclear receptors, the PPARs (PPARα/δ/γ) are of special interest in toxicology because several chemicals activate various PPARs including tributyltin, perfluoronated compounds such as PFOS, mono-2-ethylhexylphthalate, and atrazine [54, 58, 69-72]. Activation of PPARα causes peroxisome proliferation in the mouse liver, which is associated with rodent liver cancer [73,74]. However, PPARα is highly expressed in rodent liver, but weakly expressed in human liver and this difference in expression is thought to be the underlying cause of specie's differences in PPARα-mediated liver cancer, which is not observed in humans [75]. PPARγ activation is associated with obesity in multiple species. Current research suggests that PPARγ-mediated obesogens work in conjunction with RXR activation [54,76]. However, there is little data indicating that activation of the PPARs provides a toxicokinetic effect by altering the metabolism, distribution, or clearance of most chemicals.

Confirmed xenobiotic sensing nuclear receptors include the pregnane X-receptor (PXR), its relative the constitutive androstane receptor (CAR), and their invertebrate ortholog, HR96 [68, 77-83]. Because of their impact on toxicology there are extensive reviews available on the wide range of ligands and indirect activators that mediate transcriptional activation through these nuclear receptors. For an overall review of these nuclear receptors and their ligands see the following manuscripts [84-87].

PXR and CAR are primarily expessed in the liver but show limited expression in other tissues such as the intestines, urinary tract, brain, and fish gills [78, 81, 88-92]. PXR and CAR act as master regulators of phase I and phase II metabolism enzymes and phase III transporters (Figure 3). This includes CYP3A, CYP2B, UDPGT, GSTA2, SULT2A, and MRP2 [79, 93-98] with significant overlapping ligand specificities and gene regulation [86,99]. There are several manuscripts and reviews that have taken a comprehensive look at environmental chemicals, nutrients, and pharmaceuticals that activate CAR and PXR [86, 100-104].

PXR is considered promiscuous because it binds a variety of bile acids, steroids and xenobiotics in mammals, including a large number of endocrine disrupting chemicals [105-109], providing circumstantial evidence that the PXR and its close relative, CAR, are protectors of the endocrine system [3]. Xenobiotics that bind and activate PXR in mammals include rifampicin, hyperforin, bisphenol A, 4-nonylphenol, phthalic acid, 1,1-dichloro-2,2-bis (p-chlorophenyl)ethylene (DDE), methoxychlor, vinclozolin, alachlor, cyperterone acetate, trifluralin, and non-planar polychlorinated biphenyls (PCBs) [3, 79, 86, 104, 107-114].

F3
Figure 3: Function of CAR and PXR in xenobiotic metabolism. CAR and PXR are activated by specific xenobiotics (X). In turn they dimerize with RXR, act on consensus sequences (XREM/PBREM), and initiate transcription of phase I and II enzymes involved in the hydroxylation and conjugation of xenobiotics, and phase III transporters that eliminate the xenobiotics. Indirect activatin of CAR and its subsequent translocation to the nucleus is key in its transcriptional activity.

PXR binds to a larger number of diverse chemicals than other receptors [86,115]. PXR's promiscuity is attributed to its large and flexible ligand binding domain (LBD). PXR only needs to use a portion of its ligand binding pocket for chemical activation, and it has polar residues spaced through a smooth, multi-regional hydrophobic ligand-binding domain [112,116,117]. In addition, PXR has alpha helices that are flexible or can unwind, which allows for PXR to contract or expand in order to bind ligands of different sizes [117]. PXR also forms homodimers and a PXR-RXR heterotetramer complex that is crucial in the recruitment of coactivators and stabilization of the AF-2 domain [118,119].

CAR is also promiscuous, however it is for reasons related to phosphorylation rather than its binding domain. CAR's ligand binding pocket is smaller and less flexible than PXR's, and in turn CAR is less promiscuous than PXR [3,116,120,121]. TCPOBOP is one of a small number of true ligands for CAR. [122]. However, CAR can also be activated indirectly through changes in phosphorlylation status (i.e. phenobarbital) leading to translocation to the nucleus [16,123,124]. Under normal (inactivated) conditions, CAR is phosphorylated at Thr38. Dephosphorylation occurs through a Receptor for Activated C Tyrosine Kinase 1 (RACK1) - Protein Phosphatase 2 A (PP2A) cascade [125] that is inhibited by Epidermal Growth Factor (EGF) signaling [126]. Phenobarbital binds the EGFR near the EGF binding site and reduces bound EGF [127] thus inhibiting downstream actions of EGF on SRC and subsequent phosphorylation of RACK-1 allowing for increased dephosphorylation by PPA2 [126]. This blocks EGF action and increases CAR activity.

Another putative mechanism for CAR activation by phenobarbital involves AMP activated protein Kinase (AMPK) [128]. However, downstream functions such as translocation of CAR or induction of CYP2B have varied depending on the system. Inhibition of CAR translocation and CYP2B expression have also been observed following AMPK activation providing contradictory results [129]. In summary, removal of the phosphate group from Thr38 triggers nuclear translocation of CAR. CAR in turn forms a heterodimer with RXR in the nucleus and binds PBREM/DR4 enhancer modules that induce gene transcription of CYP2B6 in humans, Cyp2b10 in mice [80], along with a host of other genes required for cell growth, metabolic activity, and detoxification [86,130,131].

Given CAR and PXR's role in the induction of crucial phase I-III detoxication proteins, it is not surprising that CAR and PXR are associated with protection from anthropogenic pollutants and endobiotics. For example, CAR or PXR activation increases the metabolism, detoxication, and clearance of bile acids [132,133]. PXR expression increases in response to higher steroid levels during pregnancy presumably to protect the mother from the increased steroid load [134]. Lycopene is in part protective from atrazine toxicity due to its actions on CAR and PXR, and in turn increased metabolism of atrazine [70]. PXR also protects from benzo(a)pyrene toxicity by repressing AhR-mediated transcription [135]. CAR-null mice show significantly increased sensitivity to parathion due to decreased metabolism of parathion to p-nitrophenol, the key detoxication product of parathion [136]. In addition, PXR-null mice showed greater hepatic damage following nonylphenol exposure than wildtype mice, presumably due to a repressed transcriptional response and lower hepatic detoxication enzyme levels in PXR-null mice. PXR-null mice also had greater serum nonylphenol concentrations than wildtype mice, providing further evidence that PXR-null mice were unable to transcriptionally respond and detoxify nonylphenol [137]. Interestingly, human PXR (hPXR) mice showed responses in between wildtype and PXR-null mice indicating that hPXR is less responsive to nonylphenol than murine PXR [137]. Overall, these xenobiotics showed greater toxic effects probably due to the lack of the proper regulation or induction of key detoxification enzymes [136-139].

However, sometimes PXR or CAR activation increases metabolic activation and the toxicity of the chemical. For example, thalidomide activation of PXR increases the production of its teratogenic metabolite, 5-hydroxy-thalidomide through CYP induction [140]. PXR also mediates rifampin toxicity through its actions on aldosterone [141]. CAR-null and PXR-null mice are also less sensitive to acetaminophen, and activation of these receptors and subsequent CYP induction increases NAPQI production and toxicity [142,143]. PXR activation has also been associated with drug-drug interactions. For example, PXR activation by hyperforin increases clearance of warfarin, estradiol, and other drugs leading to reduced efficacy and poor clinical outcomes [3,111,144]. Overall, the discovery of PXR (and to a lesser extent CAR) has provided crucial information on drug-drug interactions and therefore saved lives.

HR96, as well as the C. elegans receptors, NRH48 and NHR8, are the invertebrate homologs to CAR, PXR, and VDR [51,77,145]. Similar to CAR and PXR, HR96 regulates lipid homeostasis [146-150]. HR96 also mediates the induction of phase I-III detoxication genes [68,151,152] following activation by endogenous or exogenous chemicals [68,77,83]. Recent studies indicate that activation of HR96 by atrazine provides protection from some chemicals such as docosahexaenoic acid and triclosan, but increases toxicity to others such as endosulfan and parathion [83,152]. Thus, many invertebrates also contain nuclear receptors responsive to anthropogenic stress that induce phase I-III metabolism.

1.1.3. Nrf2, AP-1 and NF-kB

Nrf2, AP-1, and NF-κB are transcription factors that respond to oxidative stress and are important regulators of GSTs, superoxide dismutase (SOD), catalase, and other protective proteins involved in the detoxification of ROS. The toxicant-induced formation of reactive oxygen species (ROS) has been associated with reduced fitness, apoptosis, cancer, and death. For example, pulp and paper mill and sewage effluents induce ROS and fatty acyl-CoA oxidase activity (an enzyme that produces the oxidant H2O2 from O2) in exposed Longnose sucker (Catostomus catostomus) [153]. Several metals including iron, copper, nickel, chromium, cadmium and possibly arsenic mediate toxic effects through oxidative mechanisms and alter redox-sensitive signaling through Nrf2, AP-1 and NF-κB [154-159]. Of these metals, chromium and arsenic have also been shown to block AP-1 and NF-κB activity by binding their respective response elements [160], and the lack of Nrf2 increases sensitivity of cells to metals and a variety of other pro-oxidants [155]. Furthermore, cadmium-induced oxidative stress increases cytochrome c and activated caspase 3, 8 and 9, causing apoptosis through the mitochondrial pathway. Anti-oxidants were able to alleviate the effects of cadmium on apoptosis demonstrating the role of ROS in cadmium-induced apoptosis [161].

The induction of antioxidant enzymes is also associated with protection from toxicants in vivo; a concept supported by the presence of a resistant population of Fundulus heteroclitus from the Elizabeth River, VA, USA that exhibits high glutathione peroxidase and reductase activities, along with high glutathione concentrations [162]. In addition, this population demonstrates both induction and a heritable increase in manganese superoxide dismutase (MnSOD) and glutathione concentrations, which may play a key role in their tolerance to PAHs [163]. Overall, the induction of anti-oxidant defenses is key in protecting individuals from chemical stress and there are three key transcription factors involved in their induction with Nrf2 as the primary protective sensor for ROS.

1.1.4. NF-κB

Nuclear factor-κB (NF-κB) is a transcription factor complex that can be activated by a number of different external signals, including several cytokines, bacterial and viral products, ultraviolet irradiation, oxidative stress, environmental chemicals such as arsenic, chromium, and diesel exhaust, and some therapeutic pharmaceuticals [164-172]. NF-κB in turn regulates the transcription of cytokines, cell adhesion molecules, stress response proteins, acute phase proteins, and regulators of apoptosis. Genes regulated by NF-κB include GSTP 1-1, COX-2, IL-1, C-reactive protein, phospholipase A2, DT-diaphorase, superoxide dismutase, α-1-antichymotrypsin, caspase 10, and IGF-BP1 [173-181] Comprehensive reviews on NF-κB can be found at [164,173], or a website maintained by Dr. Thomas Gilmore, Boston University (www.NF-kB.org).

F4
Figure 4: Activation of transcription factors by external and internal stress reponses (NF-κB). External stimuli such as environmental toxicants and oxidative stress activate IKK which phosphorylates IkB, targeting it for proteosomal degradation. The release of the inhibitory IkB allows for the NF-κB complex (RelA/p50) to enter the nucleus and initiate transcription. Interestingly, one of the genes transcribed following NF-κB activation is IkBa, which can in turn inhibit NF-κB.

NF-κB is typically found in the cytosol in its inactive state where it is bound to inhibitory IκB proteins such as IκBα. Extracellular stimuli cause the activation of IKK, a kinase that phosphorylates IκB and targets it for ubiquination and proteosomal degradation [182]. This releases the NF-κB and allows it to enter the nucleus, bind DNA and activate transcription. Interestingly, NF-κB induces the transcription of IkBα that causes an inhibitory auto-regulatory cascade. IkBα enters the nucleus following translation, binds and inactivates NF-κB, and removes it from the nucleus [183,184]. Thus, the transcriptional activation of the NF-κB pathway is often a short, transient process in cells. Figure 4 provides an overview of NF-κB action.

NF-κB refers to a family of proteins that control transcription and are involved in development, immune system functions, inflammation, cellular growth and apoptosis. Many of these proteins are referred to as Rel proteins and include RelA, Rel2, c-Rel, p105/p50, and p100/p52. The p105/p50 and p100/p52 proteins are inactive in the cell in their larger form and when the C-terminus is cleaved (p105 cleaved to p50) they become active, shorter DNA-binding proteins. The p105/p50 and p100/p52 proteins are not generally active in transcription unless bound to the Rel proteins. Rel/NF-κB proteins can regulate a large number of different genes because Rel proteins can form homodimers or heterodimers and the individual dimers have distinct DNA-binding sites. The most studied and most common of these dimers is the p50-RelA heterodimer [185].

Interestingly, NF-κB increases the transcription of several genes such as elk-1 and c-fos involved in the Activation Protein-1 (AP-1) transcriptional pathway, another sensor of oxidative stress. Thus, NF-κB can increase stress responses by activating transcription factors that bind other responses elements such as the antioxidant response element (ARE) and tetradecanoyl-phorbol-13-acetate (TPA)-response element [186]. This cross activation increases the number of genes transcribed following a stress event.

1.1.5. AP-1

Activation Protein-1 (AP-1) belongs to a family of transcription factors characterized by a basic domain and a region of leucine and hydrophobic residue repeats (bZIP family) [187]. AP-1 is a complex comprised of two main proteins, a Jun and a Fos, where Jun may include c-Jun, JunB, or JunD and Fos may include c-Fos, FosB, Fra1, or Fra2 [188]. These proteins may form homo- or heterodimers among themselves such as Jun-Jun or Jun-Fos dimers, and in turn interact with additional proteins to initiate transcription at sites containing an AP-1 consensus sequence. There are several different AP-1 DNA binding sites, including a “classical” AP-1 (TPA-response element) binding site and the antioxidant response element (ARE) [189,190].

Like NF-κB, AP-1 plays a vital role in increasing the expression of antioxidant enzymes, phase II detoxification enzymes, and cytoprotective genes in order to protect the cell from ROS. Genes thought to be regulated by AP-1 binding to the ARE include GST Ya subunits, NAD(P)H:quinine oxidoreductase (NQO1), Cu/ZnSOD, MnSOD, glutathione peroxidase, catalase, glutathione reductase, and heme oxygenase [187,191].

1.1.6. Nrf2

NF-E2 p45-related factor 2 (Nrf2) is a bZIP transcription factor with a cap'n'collar (CNC) structure that also binds several AREs [192]. Similar to NF-κB, Nrf2 is activated by the release of its inhibitor, in this case Keap-1, in the presence of ROS and then heterodimerizes with bZIP proteins such as Fos, Jun, Activating Transcription Factor-4 (ATF4), and most likely musculoaponeurotic fibrosarcoma (Maf) proteins at a variety of AREs [193-195]. AREs include classical antioxidant response elements, electrophile-response elements, β-napthoflavone-response elements, Maf-recognition elements, and AP-1 sites found within the AREs. Greater insight into all of these AREs is available in a recent review [195].

Mice lacking Nrf2 (Nrf2 -/-) show decreased mRNA transcript levels of catalase, NQO1, SOD1, heme oxygenase, stress protein A170, GST alpha and mu, and peroxiredoxin MSP 23. Furthermore, hyperoxia induced levels of NQO1, GST Ya, and glucuronosyltransferase were significantly lower in Nrf2 -/- mice compared with Nrf +/+ mice [192,196,197]. Mechanistic studies demonstrate the role of Nrf2 in the regulation of phase I-III detoxication enzymes, primarily conjugases and anti-oxidant defenses, but also MRP transporters [194, 198-200]. These studies and others [155, 156, 201-203] have made it increasingly obvious that Nrf2 is a key transcriptional regulation of oxidative balance. For example, acetaminophen is tolerated in wildtype mice at doses that kill Nrf2-null mice due to their inability to respond to oxidative stress [204].

Nrf2 is activated endogenously by a number of polyunsaturated fatty acid (PUFA) metabolites such as the oxylipins [205], including key oxo-DHA metabolites [158]. DHA, EPA, and other PUFAs are metabolized to several different oxylipins of which some activate Nrf2 such as 15-J2-IsoP [158,205]. The production of these oxylipins and subsequent activation of Nrf2 may play a protective role in several diseases including mitochondrial disfunction and cardiovascular disease [206]. Other diseases in which Nrf2 plays a protective role because of transcriptional regulation of anti-oxidant defenses include fatty liver disease, cancer, diabetes, emphysema, and chronic obstructive pulmonary disease [207-209].

Nrf2 is also activated exogenously by a host of chemicals that perturb redox status. These include several metals, PFOS, paraquat, MPTP, and other chemicals [155,156,201,210]. Nrf2 also crosstalks with the AhR and nuclear receptors such as CAR. Thus, the activation of AhR and CAR causes the subsequent activation of Nrf2 for protection of oxidative stress [194,203]. AhR or CAR activation probably activates Nrf2 due to the formation of reactive metabolites produced by CYPs following AhR/CAR-mediated CYP induction [194,203] (Figure 5). It has been hypothesized, but not definitely demonstrated, that ROS may be directly produced by specific CYPs such as Cyp2b or Cyp2e in a substrate-independent manner and this in turn activates Nrf2 [203]. More likely, Nrf2 activation following AhR or CAR-mediated CYP induction occurs due to increased ROS due to reactive metabolites or CYP-mediated oxylipin formation. The potential role of CYP induction in the activation of anti-oxidant defenses following activation by traditional xeno-sensing receptors is an interesting concept in need of more research [203]. Overall, most toxicology studies would indicate that Nrf2 is the most important of the anti-oxidant transcription factors.

F5
Figure 5: Activation of transcription factors by external and internal stress reponses (Nrf2). Reactive oxygen species modify central cysteine species on Keap-1 that leads to the decoupling of Keap-1 and Nrf2. Alternatively, Nrf2 can be phosphorylated by kinases. In turn, Nrf2 is decoupled from Keap-1 and translocates to the nucleus where it binds Maf, JunD, or ATF4 and initiates transcription of a variety of antioxidant enzymes and transporters.
1.1.7. Metal-responsive transcription factor-1 (MTF-1)

Metallothionein is primarily regulated by metal-responsive transcription factor-1 (MTF-1) [211]. Metalllthioneins (MT) are ubiquitous, low molecular weight, cysteine-rich proteins that bind and regulate the available concentrations of many metals. The primary role of MTs is to regulate concentrations of the essential trace metals, copper and zinc. At high concentrations, even essential trace metals can bind macromolecules and elicit toxicity and MT ensures a stable bioavailable population of these metals by binding excess essential metals. MT also provides protection from similar toxic metals such as Cd and Hg. For example, Cd-resistant populations of fish express high levels of metallothionein [212], and MT -/- mice show increased sensitivity to many different metals [213].

Zinc and other divalent metals bind MTF-1, which in turn binds DNA at the metal responsive element (MRE) and promotes transcription of MT. MTF-1 is also activiated by oxidative stress [214]. The promoter region of the zebrafish MT gene contains four MREs, three AP-1s and a SP-1 site. However, only the MREs and in particular the distal MRE is required for induction of MT by Zn+2, Cd+2, Cu+2, or Hg+2. MT was not induced by Ni+2, Pb+2, and Co+2 in cell culture [215]. Interestingly, while cadmium is a potent inducer of MT, it does not appear to bind MTF-1 in mammals or yeast, indicating that cadmium indirectly activates MTF-1 [216,217].

2. Biomarkers of Exposure Are often Regulated through Transcription Factors

The transcription factors described above regulate the expression of genes involved in xenobiotic responses, including several established biomarkers of chemical exposure (Table 1). It is the transcriptional regulation by chemical stress that provides the basis for many of the biomarkers. The toxicant binds to the appropriate receptor, which when bound to the promoter region of DNA, initiates the transcription of genes that can be used as biomarkers. Some of biomarkers are indicative of exposure to a specific toxicant or class of toxicants, while others are much more general and suggest oxidative or physiological stress. MT, for example, is a well established biomarker of exposure to metals due to activation of MTF-1 [211,218,219]. CYP1A induction is a well established biomarker of exposure to PAHs and HAHs and has been used as a biomarker in multiple species (AhR activation) [92,220,221]. Cyp2b and Cyp3a are biomarkers of CAR and PXR activation, respectively [78,81,222,223]. Cyp4a is induced by PPAR and vitellogenin induction provides a specific biomarker for estrogenic chemicals (estrogen receptor; ER activation)[224-226]. Although altered expression of GSTs, SOD, and other antioxidant enzymes provides information about the general physiological state or stress level of the organism, they typically do not indicate exposure to a particular toxicant, but instead production of ROS (Nrf2; other ROS sensors) [203,209]. Taken together, transcription factors provide the basis for the biomarker responses toxicologists have been measuring for decades and will continue to use.

T1

Table 1: Some currently used molecular biomarkers of exposure and the transcription factors that govern their response.

In conclusion, there are a number of crucial transcription factors that activate detoxication pathways through their regulation of key phase I-III detoxication enzymes and transporters as well as other protective proteins such as heat shock proteins, chaperones, and anti-oxidants. These transcription factors induce enzymes that protect individuals from xeno- and endobiotic stressors, including activation of AhR by members of the tryptophan-kynurenine pathway [29,227], activation of Nrf2 by oxylipins [158,205][228], activation and inactivation of PXR and CAR by steroids, steroid precursors, and bile acids [78,101,134,229], and of course numerous xenobiotic chemicals that activate all of the transcription factors mentioned previously. In conclusion, transcription factors are often an initial line of defense from toxic xeno- and endobiotics because their activation leads to a response to chemical stress that allows individuals to acclimate to the chemical insult, and therefore are the phase 0 xenobiotic response.

Acknowledgements

Research support was provided in part by National Institutes of Environmental Health Sciencs grant R15ES017321. The author would like to thank Melissa Heintz, Matt Hamilton, Emily Gessner, and Emily Olack for reading over the manuscript and providing valuable insight.

Competing Interests

The author declares no competing interests.

References

  1. R. T. Williams, “Detoxication Mechanisms: The metabolism and detoxication of drugs, toxic substances, and other organic compounds,” John Wiley & Sons, Inc., New York, NY, 2nd edition, 1959.
  2. D. L. Eaton and C. D. Klaassen, “Principles of Toxicology, in Casarett and Doull's Toxicology: The Basic Science of Poisons,” McGraw-Hill Co. Inc, New York, 1996.
  3. X. C. Kretschmer and W. S. Baldwin, “CAR and PXR: Xenosensors of endocrine disrupters?” Chemico-Biological Interactions, vol. 155, no. 3, pp. 111–128, 2005. Publisher Full Text | Google Scholar
  4. T. Ishikawa, “The ATP-dependent glutathione S-conjugate export pump,” Trends in Biochemical Sciences, vol. 17, no. 11, pp. 463–468, 1992. Publisher Full Text | Google Scholar
  5. L. J. Bain and G. A. LeBlanc, “Interaction of structurally diverse pesticides with the human MDR1 gene product P-glycoprotein,” Toxicology and Applied Pharmacology, vol. 141, no. 1, pp. 288–298, 1996. PubMed Abstract | Publisher Full Text | Google Scholar
  6. S. Karthikeyan and S. L. Hoti, “Development of fourth generation ABC inhibitors from natural products: a novel approach to overcome cancer multidrug resistance,” Anti-Cancer Agents in Medicinal Chemistry, vol. 15, no. 5, pp. 605–615, 2015. Publisher Full Text | Google Scholar
  7. M. G. Belinsky, L. J. Bain, B. B. Balsara, J. R. Testa, and G. D. Kruh, “Characterization of MOAT-C and MOAT-D, New Members of the MRP/cMOAT Subfamily of Transporter Proteins,” JNCI Journal of the National Cancer Institute, vol. 90, no. 22, pp. 1735–1741, 1998. Publisher Full Text | Google Scholar
  8. A. Mandal, V. Agrahari, V. Khurana, D. Pal, and A. K. Mitra, “Transporter effects on cell permeability in drug delivery,” Expert Opinion on Drug Delivery, vol. 14, no. 3, pp. 385–401, 2016. Publisher Full Text | Google Scholar
  9. O. M. Woodward, A. Köttgen, and M. Köttgen, “ABCG transporters and disease,” FEBS Journal, vol. 278, no. 18, pp. 3215–3225, 2011. PubMed Abstract | Publisher Full Text | Google Scholar
  10. B. Döring and E. Petzinger, “Phase 0 and phase III transport in various organs: Combined concept of phases in xenobiotic transport and metabolism,” Drug Metabolism Reviews, vol. 46, no. 3, pp. 261–282, 2014. Publisher Full Text | Google Scholar
  11. C. G. Dietrich, “Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance,” World Journal of Gastroenterology, vol. 22, no. 1, p. 72, 2016. Publisher Full Text | Google Scholar
  12. W. S. Baldwin and G. A. LeBlanc, “In vivo biotransformation of testosterone by phase I and II detoxication enzymes and their modulation by 20-hydroxyecdysone in Daphnia magna,” Aquatic Toxicology, vol. 29, no. 1-2, pp. 103–117, 1994. Publisher Full Text | Google Scholar
  13. J. D. Hayes and D. J. Pulford, “The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance,” Crit Rev Biochem Mol Biol, vol. 30, no. 6, pp. 445–600, 1995.
  14. J. Wu, J. Liu, and Z. Cai, “Determination of triclosan metabolites by using in-source fragmentation from high-performance liquid chromatography/negative atmospheric pressure chemical ionization ion trap mass spectrometry,” Rapid Communications in Mass Spectrometry, vol. 24, no. 13, pp. 1828–1834, 2010. Publisher Full Text | Google Scholar
  15. B. Lewin, Essential Genes, Pearson Prentice Hall, Upper Saddle River, NJ, 2006.
  16. S. M. Blättler, F. Rencurel, M. R. Kaufmann, and U. A. Meyer, “In the regulation of cytochrome P450 genes, phenobarbital targets LKB1 for necessary activation of AMP-activated protein kinase,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 104, no. 3, pp. 1045–1050, 2007. Publisher Full Text | Google Scholar
  17. Y. Zhou, H. Wu, M. Zhao, C. Chang, and Q. Lu, “The bach family of transcription factors: a comprehensive review,” Clinical Reviews in Allergy & Immunology, vol. 50, no. 3, pp. 345–356, 2016. Publisher Full Text | Google Scholar
  18. H. Ohi, Y. Fujita, M. Miyao, K. Saguchi, N. Murayama, and S. Higuchi, “Molecular cloning and expression analysis of the aryl hydrocarbon receptor of Xenopus laevis,” Biochemical and Biophysical Research Communications, vol. 307, no. 3, pp. 595–599, 2003. Publisher Full Text | Google Scholar
  19. J. V. Schmidt, G. H.-T. Su, J. K. Reddy, M. C. Simon, and C. A. Bradfield, “Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 93, no. 13, pp. 6731–6736, 1996. Publisher Full Text | Google Scholar
  20. R. Robles, Y. Morita, K. K. Mann et al., “The Aryl Hydrocarbon Receptor, a Basic Helix-Loop-Helix Transcription Factor of the PAS Gene Family, Is Required for Normal Ovarian Germ Cell Dynamics in the Mouse,” Endocrinology, vol. 141, no. 1, pp. 450–453, 2000. Publisher Full Text | Google Scholar
  21. E. A. Thackaberry, E. J. Bedrick, M. B. Goens et al., “Insulin regulation in AhR-null mice: embryonic cardiac enlargement, neonatal macrosomia, and altered insulin regulation and response in pregnant and aging AhR-null females,” Toxicological Sciences, vol. 76, no. 2, pp. 407–417, 2003. Publisher Full Text | Google Scholar
  22. T. Xu, Y. Zhou, and L. Qiu, “Aryl hydrocarbon receptor protects lungs from cockroach allergen-induced inflammation by modulating mesenchymal stem cells,” The Journal of Immunology, vol. 195, no. 12, pp. 5539–5550, 2015. Publisher Full Text | Google Scholar
  23. V. S. Carreira, Y. Fan, Q. Wang et al., “Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes,” Toxicological Sciences, vol. 147, no. 2, pp. 425–435, 2015. Publisher Full Text | Google Scholar
  24. H. M. Handley-Goldstone, M. W. Grow, and J. J. Stegeman, “Cardiovascular Gene Expression Profiles of Dioxin Exposure in Zebrafish Embryos,” Toxicological Sciences, vol. 85, no. 1, pp. 683–693, 2005. Publisher Full Text | Google Scholar
  25. K. A. Lanham, J. Plavicki, R. E. Peterson, and W. Heideman, “Cardiac Myocyte-Specific AHR Activation Phenocopies TCDD-Induced Toxicity in Zebrafish,” Toxicological Sciences, vol. 141, no. 1, pp. 141–154, 2014. Publisher Full Text | Google Scholar
  26. J. Chang, H. Chen, H. Su, C. Lee, and F. Folli, “Abdominal Obesity and Insulin Resistance in People Exposed to Moderate-to-High Levels of Dioxin,” PLoS ONE, vol. 11, no. 1, p. e0145818, 2016. Publisher Full Text | Google Scholar
  27. P. Lu, J. Yan, K. Liu et al., “Activation of aryl hydrocarbon receptor dissociates fatty liver from insulin resistance by inducing fibroblast growth factor 21,” Hepatology, vol. 61, no. 6, pp. 1908–1919, 2015. Publisher Full Text | Google Scholar
  28. B. Wahlang, K. C. Falkner, B. Gregory et al., “Polychlorinated biphenyl 153 is a diet-dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6/J mice,” The Journal of Nutritional Biochemistry, vol. 24, no. 9, pp. 1587–1595, 2013. Publisher Full Text | Google Scholar
  29. R. Noakes, “The Aryl Hydrocarbon Receptor: A Review of Its Role in the Physiology and Pathology of the Integument and Its Relationship to the Tryptophan Metabolism,” International Journal of Tryptophan Research, vol. 8, p. IJTR.S19985, 2015. Publisher Full Text | Google Scholar
  30. M. Machala, J. Vondráček, L. Bláha, M. Ciganek, and J. Neča, “Aryl hydrocarbon receptor-mediated activity of mutagenic polycyclic aromatic hydrocarbons determined using in vitro reporter gene assay,” Mutation Research - Genetic Toxicology and Environmental Mutagenesis, vol. 497, no. 1-2, pp. 49–62, 2001. Publisher Full Text | Google Scholar
  31. S. Safe, “Polychlorinated biphenyls (PCBs), dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and related compounds: Environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs),” Critical Reviews in Toxicology, vol. 21, no. 1, pp. 51–88, 1990. PubMed Abstract | Publisher Full Text | Google Scholar
  32. M.S. and D. Phelan Denison, The Ah Receptor Signal Transduction Pathway, in Toxicant-Receptor Interactions, M.S. Denison and W.G. Helferich, Editors. 1998, Taylor and Francis: Philadelphia, PA. p. 243.
  33. S. Ernest and E. Bello-Reuss, “P-glycoprotein functions and substrates: Possible roles of MDR1 gene in the kidney,” Kidney International Supplements, vol. 53, no. 65, pp. S11–S17, 1998. PubMed Abstract
  34. K. W. Bock and C. Köhle, “Ah receptor- and TCDD-mediated liver tumor promotion: clonal selection and expansion of cells evading growth arrest and apoptosis,” Biochemical Pharmacology, vol. 69, no. 10, pp. 1403–1408, 2005. Publisher Full Text | Google Scholar
  35. G. I. Sunahara, “Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated decreases in dexamethasone binding to rat hepatic cytosolic glucocorticoid receptor,” Mol Pharmacol, pp. 36–239, 1989.
  36. M. DeVito, T. Thomas, E. Martin, T. Umbreit, and M. Gallo, “Antiestrogenic action of 2,3,7,8-tetrachlorodibenzo-p-dioxin: Tissue-specific regulation of estrogen receptor in CD1 mice,” Toxicology and Applied Pharmacology, vol. 113, no. 2, pp. 284–292, 1992. Publisher Full Text | Google Scholar
  37. J. R. Petrulis, N. G. Hord, and G. H. Perdew, “Subcellular Localization of the Aryl Hydrocarbon Receptor Is Modulated by the Immunophilin Homolog Hepatitis B Virus X-associated Protein 2,” The Journal of Biological Chemistry, vol. 275, no. 48, pp. 37448–37453, 2000. Publisher Full Text | Google Scholar
  38. G. Vázquez-Gómez, L. Rocha-Zavaleta, M. Rodríguez-Sosa, P. Petrosyan, and J. Rubio-Lightbourn, “Benzo[a]pyrene activates an AhR/Src/ERK axis that contributes to CYP1A1 induction and stable DNA adducts formation in lung cells,” Toxicology Letters, vol. 289, pp. 54–62, 2018. Publisher Full Text | Google Scholar
  39. J. P. Incardona, T. L. Linbo, and N. L. Scholz, “Cardiac toxicity of 5-ring polycyclic aromatic hydrocarbons is differentially dependent on the aryl hydrocarbon receptor 2 isoform during zebrafish development,” Toxicology and Applied Pharmacology, vol. 257, no. 2, pp. 242–249, 2011. Publisher Full Text | Google Scholar
  40. J. Mimura, K. Yamashita, K. Nakamura et al., “Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor,” Genes to Cells, vol. 2, no. 10, pp. 645–654, 1997. Publisher Full Text | Google Scholar
  41. J. M. Peters, M. G. Narotsky, G. Elizondo, P. M. Fernandez-Salguero, F. J. Gonzalez, and B. D. Abbott, “Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-null mice,” Toxicological Sciences, vol. 47, no. 1, pp. 86–92, 1999. Publisher Full Text | Google Scholar
  42. J. A. Lavine, A. J. Rowatt, T. Klimova et al., “Aryl Hydrocarbon Receptors in the Frog Xenopus laevis: Two AhR1 Paralogs Exhibit Low Affinity for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD),” Toxicological Sciences, vol. 88, no. 1, pp. 60–72, 2005. Publisher Full Text | Google Scholar
  43. A. M. Reitzel, S. I. Karchner, D. G. Franks et al., “Genetic variation at aryl hydrocarbon receptor (AHR) loci in populations of Atlantic killifish (Fundulus heteroclitus) inhabiting polluted and reference habitats,” BMC Evolutionary Biology, vol. 14, no. 1, p. 6, 2014. Publisher Full Text | Google Scholar
  44. X. Arzuaga, W. Calcaño, and A. Elskus, “The DNA de-methylating agent 5-azacytidine does not restore CYP1A induction in PCB resistant Newark Bay killifish (Fundulus heteroclitus),” Marine Environmental Research, vol. 58, no. 2-5, pp. 517–520, 2004. Publisher Full Text | Google Scholar
  45. M. E. Hahn, S. I. Karchner, D. G. Franks, and R. R. Merson, “Aryl hydrocarbon receptor polymorphisms and dioxin resistance in Atlantic killifish (Fundulus heteroclitus),” Pharmacogenetics, vol. 14, no. 2, pp. 131–143, 2004. PubMed Abstract | Publisher Full Text | Google Scholar
  46. S. M. Bello, D. G. Franks, J. J. Stegeman, and M. E. Hahn, “Acquired resistance to Ah receptor agonists in a population of Atlantic killifish (Fundulus heteroclitus) inhabiting a marine Superfund site: In vivo and in vitro studies on the inducibility of xenobiotic metabolizing enzymes,” Toxicological Sciences, vol. 60, no. 1, pp. 77–91, 2001. PubMed Abstract | Publisher Full Text | Google Scholar
  47. J. N. Meyer, “Cytochrome P4501A (CYP1A) in Killifish (Fundulus heteroclitus): Heritability of Altered Expression and Relationship to Survival in Contaminated Sediments,” Toxicological Sciences, vol. 68, no. 1, pp. 69–81. Publisher Full Text | Google Scholar
  48. D. E. Nacci, M. Kohan, M. Pelletier, and E. George, “Effects of benzo[a]pyrene exposure on a fish population resistant to the toxic effects of dioxin-like compounds,” Aquatic Toxicology, vol. 57, no. 4, pp. 203–215, 2002. Publisher Full Text | Google Scholar
  49. N. Aluru, S. I. Karchner, D. G. Franks, D. Nacci, D. Champlin, and M. E. Hahn, “Targeted mutagenesis of aryl hydrocarbon receptor 2a and 2b genes in Atlantic killifish (Fundulus heteroclitus),” Aquatic Toxicology, vol. 158, pp. 192–201, 2015. Publisher Full Text | Google Scholar
  50. Y. Zhao, K. Zhang, J. P. Giesy, and J. Hu, “Families of nuclear receptors in vertebrate models: characteristic and comparative toxicological perspective,” Scientific Reports, vol. 5, article 8554, 2015. Publisher Full Text | Google Scholar
  51. E. J. Litoff, T. E. Garriott, G. K. Ginjupalli et al., “Annotation of the Daphnia magna nuclear receptors: Comparison to Daphnia pulex,” Gene, vol. 552, no. 1, pp. 116–125, 2014. Publisher Full Text | Google Scholar
  52. R. M. Evans, “The Nuclear Receptor Superfamily: A Rosetta Stone for Physiology,” Molecular Endocrinology, vol. 19, no. 6, pp. 1429–1438, 2005. Publisher Full Text | Google Scholar
  53. F. Echeverría, M. Ortiz, R. Valenzuela, and L. A. Videla, “Long-chain polyunsaturated fatty acids regulation of PPARs, signaling: Relationship to tissue development and aging,” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 114, pp. 28–34, 2016. Publisher Full Text | Google Scholar
  54. B. M. Shoucri, E. S. Martinez, T. J. Abreo et al., “Retinoid X Receptor Activation Alters the Chromatin Landscape To Commit Mesenchymal Stem Cells to the Adipose Lineage,” Endocrinology, vol. 158, no. 10, pp. 3109–3125, 2017. Publisher Full Text | Google Scholar
  55. A. le Maire, M. Grimaldi, D. Roecklin et al., “Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors,” EMBO Reports, vol. 10, no. 4, pp. 367–373, 2009. Publisher Full Text | Google Scholar
  56. L. Yue, F. Ye, C. Gui et al., “Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation,” Protein Science, vol. 14, no. 3, pp. 812–822, 2005. Publisher Full Text | Google Scholar
  57. J. Jeske, A. Bitter, W. E. Thasler, T. S. Weiss, M. Schwab, and O. Burk, “Ligand-dependent and -independent regulation of human hepatic sphingomyelin phosphodiesterase acid-like 3A expression by pregnane X receptor and crosstalk with liver X receptor,” Biochemical Pharmacology, vol. 136, pp. 122–135, 2017. Publisher Full Text | Google Scholar
  58. G. A. LeBlanc, “Detailed Review Paper on the State of the Science on Novel In Vitro and In Vivo Screening and Testing Methods and Endpoints for Evaluating Endocdrine Disruptors in Series on Testing Assessment: No. 178,” in Organisation for Economic Co-operation and Development: Paris, p. 213, Organisation for Economic Co-operation and Development, Paris, 2012.
  59. B. L. Urquhart, R. G. Tirona, and R. B. Kim, “Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs,” The Journal of Clinical Pharmacology, vol. 47, no. 5, pp. 566–578, 2007. Publisher Full Text | Google Scholar
  60. L. Malerød, M. Sporstøl, L. K. Juvet et al., “Bile acids reduce SR-BI expression in hepatocytes by a pathway involving FXR/RXR, SHP, and LRH-1,” Biochemical and Biophysical Research Communications, vol. 336, no. 4, pp. 1096–1105, 2005. Publisher Full Text | Google Scholar
  61. D. L. Howarth, L. R. Hagey, S. H. Law et al., “Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro,” Aquatic Toxicology, vol. 98, no. 3, pp. 245–255, 2010. Publisher Full Text | Google Scholar
  62. E. J. Reschly, N. Ai, S. Ekins et al., “Evolution of the bile salt nuclear receptor FXR in vertebrates,” Journal of Lipid Research, vol. 49, no. 7, pp. 1577–1587, 2008. Publisher Full Text | Google Scholar
  63. T. Matsubara, F. Li, and F. J. Gonzalez, “FXR signaling in the enterohepatic system,” Molecular and Cellular Endocrinology, vol. 368, no. 1-2, pp. 17–29, 2013. Publisher Full Text | Google Scholar
  64. K. H. Kim, J. M. Choi, F. Li et al., “Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis,” Endocrinology, vol. 159, no. 6, pp. 2435–2446, 2018. Publisher Full Text | Google Scholar
  65. X. Li, Z. Wang, and J. E. Klaunig, “The effects of perfluorooctanoate on high fat diet induced non-alcoholic fatty liver disease in mice,” Toxicology, vol. 416, pp. 1–14, 2019. Publisher Full Text | Google Scholar
  66. T. H. Lindblom, G. J. Pierce, and A. E. Sluder, “A C. elegans orphan nuclear receptor contributes to xenobiotic resistance,” Current Biology, vol. 11, no. 11, pp. 864–868, 2001. Publisher Full Text | Google Scholar
  67. Y. Li, G. K. Ginjupalli, and W. S. Baldwin, “The HR97 (NR1L) group of nuclear receptors: A new group of nuclear receptors discovered in Daphnia species,” General and Comparative Endocrinology, vol. 206, pp. 30–42, 2014. Publisher Full Text | Google Scholar
  68. K. King-Jones, M. A. Horner, G. Lam, and C. S. Thummel, “The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila,” Cell Metabolism, vol. 4, no. 1, pp. 37–48, 2006. Publisher Full Text | Google Scholar
  69. E. K. Maloney and D. J. Waxman, “trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals,” Toxicology and Applied Pharmacology, vol. 161, no. 2, pp. 209–218, 1999. Publisher Full Text | Google Scholar
  70. J. Xia, J. Lin, X. Li et al., “Atrazine-induced environmental nephrosis was mitigated by lycopene via modulating nuclear xenobiotic receptors-mediated response,” The Journal of Nutritional Biochemistry, vol. 51, pp. 80–90, 2018. Publisher Full Text | Google Scholar
  71. C. H. Hurst and D. J. Waxman, “Activation of, pp. ARa-ARand,” pp. ARg-ARby environmental phthalate monesters. Toxicol Sci, vol. 74, pp. 297–308, 2003.
  72. S. C. Yanik, A. H. Baker, K. K. Mann, and J. J. Schlezinger, “Organotins are potent activators of PPARγ and adipocyte differentiation in bone marrow multipotent mesenchymal stromal cells,” Toxicological Sciences, vol. 122, no. 2, pp. 476–488, 2011. Publisher Full Text | Google Scholar
  73. P. R. Holden and J. D. Tugwood, “Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences,” Molecular Endocrinology, vol. 22, no. 1, pp. 1–8, 1999. Publisher Full Text | Google Scholar
  74. E. E. Hatch, “Cancer Risk in Women Exposed to Diethylstilbestrol In Utero,” Journal of the American Medical Association, vol. 280, no. 7, p. 630, 1998. Publisher Full Text | Google Scholar
  75. F. J. Gonzalez and Y. M. Shah, “PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators,” Toxicology, vol. 246, no. 1, pp. 2–8, 2008. Publisher Full Text | Google Scholar
  76. Y. H. Wang, G. Kwon, H. Li, and G. A. LeBlanc, “Tributyltin Synergizes with 20-Hydroxyecdysone to Produce Endocrine Toxicity,” Toxicological Sciences, vol. 123, no. 1, pp. 71–79, 2011. Publisher Full Text | Google Scholar
  77. E. Karimullina, “HR96 is a promiscuous endo- and xeno-sensing nuclear receptor,” Aquat Toxicol, pp. 116–117, 2012.
  78. S. A. Kliewer, J. T. Moore, L. Wade et al., “An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway,” Cell, vol. 92, no. 1, pp. 73–82, 1998. Publisher Full Text | Google Scholar
  79. B. Blumberg, W. Sabbagh Jr., H. Juguilon et al., “SXR, a novel steroid and xenobiotic-sensing nuclear receptor,” Genes & Development, vol. 12, no. 20, pp. 3195–3205, 1998. Publisher Full Text | Google Scholar
  80. P. Honkakoski, I. Zelko, T. Sueyoshi, and M. Negishi, “The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene,” Molecular and Cellular Biology, vol. 18, no. 10, pp. 5652–5658, 1998. Publisher Full Text | Google Scholar
  81. P. Wei, J. Zhang, M. Egan-Hafley, S. Liang, and D. D. Moore, “The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism,” Nature, vol. 407, no. 6806, pp. 920–923, 2000. Publisher Full Text | Google Scholar
  82. S. Afschar et al., “Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila,” Proc Natl Acad Sci U S A, vol. 113, no. 5, pp. 1321–1326, 2016.
  83. A. M. Schmidt, N. Sengupta, C. A. Saski, R. E. Noorai, and W. S. Baldwin, “RNA sequencing indicates that atrazine induces multiple detoxification genes in Daphnia magna and this is a potential source of its mixture interactions with other chemicals,” Chemosphere, vol. 189, pp. 699–708, 2017. PubMed Abstract | Publisher Full Text | Google Scholar
  84. A. Chawta, J. J. Repa, R. M. Evans, and D. J. Mangelsdorf, “Nuclear receptors and lipid physiology: opening the x-files,” Science, vol. 294, no. 5548, pp. 1866–1870, 2001. Publisher Full Text | Google Scholar
  85. E. S. Tien and M. Negishi, “Nuclear receptors CAR and PXR in the regulation of hepatic metabolism,” Xenobiotica, vol. 36, no. 10-11, pp. 1152–1163, 2009. Publisher Full Text | Google Scholar
  86. J. Hernandez, L. Mota, and W. Baldwin, “Activation of CAR and PXR by Dietary, Environmental and Occupational Chemicals Alters Drug Metabolism, Intermediary Metabolism, and Cell Proliferation,” Current Pharmacogenomics and Personalized Medicine, vol. 7, no. 2, pp. 81–105, 2009. Publisher Full Text | Google Scholar
  87. C. Xu, M. Huang, and H. Bi, “PXR- and CAR-mediated herbal effect on human diseases,” Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1859, no. 9, pp. 1121–1129, 2016. Publisher Full Text | Google Scholar
  88. S. Dauchy, F. Dutheil, R. J. Weaver et al., “ABC transporters, cytochromes P450 and their main transcription factors: expression at the human blood-brain barrier,” Journal of Neurochemistry, vol. 107, no. 6, pp. 1518–1528, 2008. Publisher Full Text | Google Scholar
  89. C. A. Frye, C. J. Koonce, A. A. Walf, and J. C. Rusconi, “Motivated behaviors and levels of 3α,5α-THP in the midbrain are attenuated by knocking down expression of pregnane xenobiotic receptor in the midbrain ventral tegmental area of proestrous rats,” The Journal of Sexual Medicine, vol. 10, no. 7, pp. 1692–1706, 2013. Publisher Full Text | Google Scholar
  90. J. M. Maglich, J. A. Caravella, M. H. Lambert, T. M. Willson, J. T. Moore, and L. Ramamurthy, “The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily,” Nucleic Acids Research, vol. 31, no. 14, pp. 4051–4058, 2003. PubMed Abstract | Publisher Full Text | Google Scholar
  91. I. M. Booth Depaz, F. Toselli, P. A. Wilce, and E. M. Gillam, “Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls,” Drug Metabolism and Disposition, vol. 41, no. 6, pp. 1187–1194, 2013. Publisher Full Text | Google Scholar
  92. F. Toselli, I. De Waziers, M. Dutheil et al., “Gene expression profiling of cytochromes P450, ABC transporters and their principal transcription factors in the amygdala and prefrontal cortex of alcoholics, smokers and drug-free controls by qRT-PCR,” Xenobiotica, vol. 45, no. 12, pp. 1129–1137, 2015. Publisher Full Text | Google Scholar
  93. E. L. LeCluyse, “Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics,” Chemico-Biological Interactions, vol. 134, no. 3, pp. 283–289, 2001. Publisher Full Text | Google Scholar
  94. H.-M. Kauffmann, S. Pfannschmidt, H. Zöller et al., “Influence of redox-active compounds and PXR-activators on human MRP1 and MRP2 gene expression,” Toxicology, vol. 171, no. 2-3, pp. 137–146, 2002. PubMed Abstract | Publisher Full Text | Google Scholar
  95. K. C. Falkner, “Regulation of the rat glutathione S-transferase A2 gene by glucocorticoids: involvement of both the glucocorticoid and pregnane X receptors,” Mol Pharmacol, vol. 60, no. 3, pp. 611–619, 2001.
  96. J. Sonoda, W. Xie, J. M. Rosenfeld, J. L. Barwick, P. S. Guzelian, and R. M. Evans, “Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR),” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 99, no. 21, pp. 13801–13806, 2002. Publisher Full Text | Google Scholar
  97. Z. Duanmu, D. Locke, J. Smigelski et al., “Effects of Dexamethasone on Aryl (SULT1A1)- and Hydroxysteroid (SULT2A1)-Sulfotransferase Gene Expression in Primary Cultured Human Hepatocytes,” Drug Metabolism and Disposition, vol. 30, no. 9, pp. 997–1004, 2002. Publisher Full Text | Google Scholar
  98. C. Chen, J. L. Staudinger, and C. D. Klaassen, “Nuclear Receptor, Pregnane X Receptor, is Required for Induction of UDP-Glucuronosyltransferases in Mouse Liver by Pregnenolone-16α-Carbonitrile,” Drug Metabolism and Disposition, vol. 31, no. 7, pp. 908–915, 2003. Publisher Full Text | Google Scholar
  99. L. B. Moore, D. J. Parks, S. A. Jones et al., “Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands,” The Journal of Biological Chemistry, vol. 275, no. 20, pp. 15122–15127, 2000. Publisher Full Text | Google Scholar
  100. M. R. Milnes, A. Garcia, E. Grossman et al., “Activation of Steroid and Xenobiotic Receptor (SXR, NR1I2) and Its Orthologs in Laboratory, Toxicologic, and Genome Model Species,” Environmental Health Perspectives, vol. 116, no. 7, pp. 880–885, 2008. Publisher Full Text | Google Scholar
  101. W. S. Baldwin and J. A. Roling, “A Concentration Addition Model for the Activation of the Constitutive Androstane Receptor by Xenobiotic Mixtures,” Toxicological Sciences, vol. 107, no. 1, pp. 93–105, 2009. Publisher Full Text | Google Scholar
  102. H. Yamada, Y. Ishii, M. Yamamoto, and K. Oguri, “Induction of the Hepatic Cytochrome P450 2B Subfamily by Xenobiotics: Research History, Evolutionary Aspect, Relation to Tumorigenesis, and Mechanism,” Current Drug Metabolism, vol. 7, no. 4, pp. 397–409, 2006. Publisher Full Text | Google Scholar
  103. M. Sinz, S. Kim, Z. Zhu et al., “Evaluation of 170 Xenobiotics as Transactivators of Human Pregnane X Receptor (hPXR) and Correlation to Known CYP3A4 Drug Interactions,” Current Drug Metabolism, vol. 7, no. 4, pp. 375–388, 2006. Publisher Full Text | Google Scholar
  104. S. J. Shukla, S. Sakamuru, R. Huang et al., “Identification of Clinically Used Drugs That Activate Pregnane X Receptors,” Drug Metabolism and Disposition, vol. 39, no. 1, pp. 151–159, 2010. Publisher Full Text | Google Scholar
  105. W. Xie, A. Radominska-Pandya, Y. Shi et al., “An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 98, no. 6, pp. 3375–3380, 2001. Publisher Full Text | Google Scholar
  106. J. Sonoda, L. W. Chong, M. Downes et al., “Pregnane X receptor prevents hepatorenal toxicity from cholesterol metabolites,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 102, no. 6, pp. 2198–2203, 2005. Publisher Full Text | Google Scholar
  107. E. Mikamo, S. Harada, J. Nishikawa, and T. Nishihara, “Endocrine disruptors induce cytochrome P450 by affecting transcriptional regulation via pregnane X receptor,” Toxicology and Applied Pharmacology, vol. 193, no. 1, pp. 66–72, 2003. Publisher Full Text | Google Scholar
  108. M. E. Wyde, E. Bartolucci, A. Ueda et al., “The environmental pollutant 1,1-Dichloro-2,2-bis (p-chlorophenyl)ethylene induces rat hepatic cytochrome P450 2B and 3A expression through the constitutive androstane receptor and pregnane X receptor,” Molecular Pharmacology, vol. 64, no. 2, pp. 474–481, 2003. Publisher Full Text | Google Scholar
  109. H. Masuyama, “Endocrine Disrupting Chemicals, Phthalic Acid and Nonylphenol, Activate Pregnane X Receptor-Mediated Transcription,” Molecular Endocrinology, vol. 14, no. 3, pp. 421–428, 2000. Publisher Full Text | Google Scholar
  110. E. G. Schuetz, C. Brimer, and J. D. Schuetz, “ Environmental Xenobiotics and the Antihormones Cyproterone Acetate and Spironolactone Use the Nuclear Hormone Pregnenolone X Receptor to Activate the CYP3A23 Hormone Response Element ,” Molecular Pharmacology, vol. 54, no. 6, pp. 1113–1117, 1998. Publisher Full Text | Google Scholar
  111. G. Vogel, “PHARMACOLOGY: A Worrisome Side Effect of an Antianxiety Remedy,” Science, vol. 291, no. 5501, pp. 37–37. Publisher Full Text | Google Scholar
  112. S. Ekins and J. A. Erickson, “A pharmacophore for human pregnane X receptor ligands,” Drug Metabolism and Disposition, vol. 30, no. 1, pp. 96–99, 2002. Publisher Full Text | Google Scholar
  113. J. P. Hernandez, W. Huang, L. M. Chapman, S. Chua, D. D. Moore, and W. S. Baldwin, “The Environmental Estrogen, Nonylphenol, Activates the Constitutive Androstane Receptor,” Toxicological Sciences, vol. 98, no. 2, pp. 416–426, 2007. Publisher Full Text | Google Scholar
  114. M. N. Jacobs, G. T. Nolan, and S. R. Hood, “Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR),” Toxicology and Applied Pharmacology, vol. 209, no. 2, pp. 123–133, 2005. Publisher Full Text | Google Scholar
  115. J. Wang, S. Dai, Y. Guo, W. Xie, and Y. Zhai, “Biology of PXR: Role in drug-hormone interactions,” EXCLI Journal, vol. 13, pp. 728–739, 2014.
  116. R. E. Watkins, G. B. Wisely, L. B. Moore et al., “The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity,” Science, vol. 292, no. 5525, pp. 2329–2333, 2001. Publisher Full Text | Google Scholar
  117. S. Suzuki, N. Suzuki, J. Mori, A. Oshima, S. Usami, and K. Hashizume, “micro-Crystallin as an intracellular 3,5,3##hssm###x2032;-triiodothyronine holder in vivo,” Molecular Endocrinology, vol. 21, no. 4, pp. 885–894, 2007. Publisher Full Text | Google Scholar
  118. B. D. Wallace, “Structural and functional analysis of the human nuclear xenobiotic receptor PXR in complex with RXRa,” J Mol Biol, vol. 425, no. 14, pp. 2561–2577, 2013.
  119. D. G. Teotico, M. L. Frazier, F. Ding et al., “Active Nuclear Receptors Exhibit Highly Correlated AF-2 Domain Motions,” PLoS Computational Biology, vol. 4, no. 7, p. e1000111, 2008. Publisher Full Text | Google Scholar
  120. K. Suino, L. Peng, R. Reynolds et al., “The Nuclear Xenobiotic Receptor CARStructural Determinants of Constitutive Activation and Heterodimerization,” Molecular Cell, vol. 16, no. 6, pp. 893–905, 2004. Publisher Full Text | Google Scholar
  121. J. Gao and W. Xie, “Pregnane X Receptor and Constitutive Androstane Receptor at the Crossroads of Drug Metabolism and Energy Metabolism,” Drug Metabolism and Disposition, vol. 38, no. 12, pp. 2091–2095, 2010. Publisher Full Text | Google Scholar
  122. I. Tzameli, P. Pissios, E. G. Schuetz, and D. D. Moore, “The Xenobiotic Compound 1,4-Bis[2-(3,5-Dichloropyridyloxy)]Benzene Is an Agonist Ligand for the Nuclear Receptor CAR,” Molecular and Cellular Biology, vol. 20, no. 9, pp. 2951–2958, 2000. Publisher Full Text | Google Scholar
  123. K. Yoshinori et al., “Identification of the nuclear receptor CAR: HSP90 complex in mouse liver and recruitment of protein phosphotase 2A in response to phenobarbital,” FEBS Lett, vol. 548, pp. 17–20, 2003.
  124. F. Hosseinpour, R. Moore, M. Negishi, and T. Sueyoshi, “Serine 202 Regulates the Nuclear Translocation of Constitutive Active/Androstane Receptor,” Molecular Pharmacology, vol. 69, no. 4, pp. 1095–1102, 2006. Publisher Full Text | Google Scholar
  125. K. Yoshinari, K. Kobayashi, R. Moore, T. Kawamoto, and M. Negishi, “Identification of the nuclear receptor CAR:HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital,” FEBS Letters, vol. 548, no. 1-3, pp. 17–20, 2003. Publisher Full Text | Google Scholar
  126. S. Mutoh, M. Sobhany, R. Moore et al., “Phenobarbital Indirectly Activates the Constitutive Active Androstane Receptor (CAR) by Inhibition of Epidermal Growth Factor Receptor Signaling,” Science Signaling, vol. 6, no. 274, pp. ra31–ra31, 2013. Publisher Full Text | Google Scholar
  127. S. A. Meyer and R. L. Jirtle, “Old Dance with a New Partner: EGF Receptor as the Phenobarbital Receptor Mediating Cyp2B Expression,” Science Signaling, vol. 6, no. 274, pp. pe16–pe16, 2013. Publisher Full Text | Google Scholar
  128. F. Rencurel, A. Stenhouse, S. A. Hawley et al., “AMP-activated Protein Kinase Mediates Phenobarbital Induction of CYP2B Gene Expression in Hepatocytes and a Newly Derived Human Hepatoma Cell Line,” The Journal of Biological Chemistry, vol. 280, no. 6, pp. 4367–4373, 2005. Publisher Full Text | Google Scholar
  129. H. Yang and H. Wang, “Signaling control of the constitutive androstane receptor (CAR),” Protein & Cell, vol. 5, no. 2, pp. 113–123, 2014. Publisher Full Text | Google Scholar
  130. A. Ueda, H. K. Hamadeh, H. K. Webb et al., “Diverse Roles of the Nuclear Orphan Receptor CAR in Regulating Hepatic Genes in Response to Phenobarbital,” Molecular Pharmacology, vol. 61, no. 1, pp. 1–6, 2002. Publisher Full Text | Google Scholar
  131. B. Niu, D. M. Coslo, A. R. Bataille, I. Albert, B. F. Pugh, and C. J. Omiecinski, “In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets,” Nucleic Acids Research, vol. 46, no. 16, pp. 8385–8403, 2018. Publisher Full Text | Google Scholar
  132. X. Wang, F. Wang, Z. Lu, X. Jin, and Y. Zhang, “Semi-quantitative profiling of bile acids in serum and liver reveals the dosage-related effects of dexamethasone on bile acid metabolism in mice,” Journal of Chromatography B, vol. 1095, pp. 65–74, 2018. Publisher Full Text | Google Scholar
  133. S. P. Saini, J. Sonoda, L. Xu et al., “A Novel Constitutive Androstane Receptor-Mediated and CYP3A-Independent Pathway of Bile Acid Detoxification,” Molecular Pharmacology, vol. 65, no. 2, pp. 292–300, 2004. Publisher Full Text | Google Scholar
  134. H. Masuyama, Y. Hiramatsu, Y. Mizutani, H. Inoshita, and T. Kudo, “The expression of pregnane X receptor and its target gene, cytochrome P450 3A1, in perinatal mouse,” Molecular and Cellular Endocrinology, vol. 172, no. 1-2, pp. 47–56, 2001. Publisher Full Text | Google Scholar
  135. H. Cui, X. Gu, J. Chen et al., “Pregnane X receptor regulates the AhR/Cyp1A1 pathway and protects liver cells from benzo-[α]-pyrene-induced DNA damage,” Toxicology Letters, vol. 275, pp. 67–76, 2017. Publisher Full Text | Google Scholar
  136. L. C. Mota, J. P. Hernandez, and W. S. Baldwin, “Constitutive androgen receptor-null mice are sensitive to the toxic effects of parathion: Association with reduced cytochrome P450-mediated parathion metabolism,” Drug Metabolism and Disposition, vol. 38, no. 9, pp. 1582–1588, 2010. PubMed Abstract | Publisher Full Text | Google Scholar
  137. L. C. Mota, C. Barfield, J. P. Hernandez, and W. S. Baldwin, “Nonylphenol-mediated CYP induction is PXR-dependent: The use of humanized mice and human hepatocytes suggests that hPXR is less sensitive than mouse PXR to nonylphenol treatment,” Toxicology and Applied Pharmacology, vol. 252, no. 3, pp. 259–267, 2011. Publisher Full Text | Google Scholar
  138. J. Hernandez, L. Mota, W. Huang, D. Moore, and W. Baldwin, “Sexually dimorphic regulation and induction of P450s by the constitutive androstane receptor (CAR),” Toxicology, vol. 256, no. 1-2, pp. 53–64, 2009. Publisher Full Text | Google Scholar
  139. R. Kumar, L. C. Mota, E. J. Litoff et al., “Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice,” PLoS ONE, vol. 12, no. 3, p. e0174355, 2017. Publisher Full Text | Google Scholar
  140. N. Murayama, Y. Kazuki, D. Satoh et al., “Induction of human cytochrome P450 3A enzymes in cultured placental cells by thalidomide and relevance to bioactivation and toxicity,” The Journal of Toxicological Sciences, vol. 42, no. 3, pp. 343–348, 2017. Publisher Full Text | Google Scholar
  141. Y. Zhai, H. V. Pai, J. Zhou, J. A. Amico, R. R. Vollmer, and W. Xie, “Activation of Pregnane X Receptor Disrupts Glucocorticoid and Mineralocorticoid Homeostasis,” Molecular Endocrinology, vol. 21, no. 1, pp. 138–147, 2007. Publisher Full Text | Google Scholar
  142. C. Wang, W. Xu, Y. Zhang, D. Huang, and K. Huang, “Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity,” Cell Death & Disease, vol. 9, no. 8, 2018. Publisher Full Text | Google Scholar
  143. J. Zhang, W. Huang, S. S. Chua, P. Wei, and D. D. Moore, “Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR,” Science, vol. 298, no. 5592, pp. 422–424, 2002. Publisher Full Text | Google Scholar
  144. W. Xie, “Induction of P450s through PXR,” in Proceedings of the in 34th Gordon Research Conference on Drug Metabolism, Holderness School, Plymouth NH, 2004.
  145. S. A. Thomson, W. S. Baldwin, Y. H. Wang, G. Kwon, and G. A. LeBlanc, “Annotation, phylogenetics, and expression of the nuclear receptors in Daphnia pulex,” BMC Genomics, vol. 10, no. 1, p. 500, 2009. Publisher Full Text | Google Scholar
  146. M. A. Horner, K. Pardee, S. Liu et al., “The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis,” Genes & Development, vol. 23, no. 23, pp. 2711–2716, 2009. Publisher Full Text | Google Scholar
  147. M. H. Sieber and C. S. Thummel, “The DHR96 Nuclear Receptor Controls Triacylglycerol Homeostasis in Drosophila,” Cell Metabolism, vol. 10, no. 6, pp. 481–490, 2009. Publisher Full Text | Google Scholar
  148. M. Sieber and C. Thummel, “Coordination of Triacylglycerol and Cholesterol Homeostasis by DHR96 and the Drosophila LipA Homolog magro,” Cell Metabolism, vol. 15, no. 1, pp. 122–127, 2012. Publisher Full Text | Google Scholar
  149. N. Sengupta, P. D. Gerard, and W. S. Baldwin, “Perturbations in polar lipids, starvation survival and reproduction following exposure to unsaturated fatty acids or environmental toxicants in Daphnia magna,” Chemosphere, vol. 144, pp. 2302–2311, 2016. Publisher Full Text | Google Scholar
  150. N. Sengupta, D. C. Reardon, P. D. Gerard, and W. S. Baldwin, “Exchange of polar lipids from adults to neonates in Daphnia magna: Perturbations in sphingomyelin allocation by dietary lipids and environmental toxicants,” PLoS ONE, vol. 12, no. 5, 2017.
  151. G. G. Lin, T. Kozaki, and J. G. Scott, “Hormone receptor-like in 96 and Broad-Complex modulate phenobarbital induced transcription of cytochrome P450 CYP6D1 in Drosophila S2 cells,” Insect Molecular Biology, vol. 20, no. 1, pp. 87–95, 2011. Publisher Full Text | Google Scholar
  152. N. Sengupta, E. J. Litoff, and W. S. Baldwin, “The HR96 activator, atrazine, reduces sensitivity of D. magna to triclosan and DHA,” Chemosphere, vol. 128, pp. 299–306, 2015. Publisher Full Text | Google Scholar
  153. K. Oakes, “Oxidative stress responses in longnose sucker (Catostomus catostomus) exposed to pulp and paper mill and municipal sewage effluents,” Aquatic Toxicology, vol. 67, no. 3, pp. 255–271, 2004. Publisher Full Text | Google Scholar
  154. G. S. Buzard and K. S. Kasprzak, “Possible roles of nitric oxide and redox cell signaling in metal-induced toxicity and carcinogenesis: a review,” J Environ Pathol Toxicol Oncol, vol. 19, no. 3, pp. 179–199, 2000.
  155. L. E. Tebay, H. Robertson, S. T. Durant et al., “Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease,” Free Radical Biology & Medicine, vol. 88, pp. 108–146, 2015. Publisher Full Text | Google Scholar
  156. J. Xu, P. Shimpi, L. Armstrong, D. Salter, and A. L. Slitt, “PFOS induces adipogenesis and glucose uptake in association with activation of Nrf2 signaling pathway,” Toxicology and Applied Pharmacology, vol. 290, pp. 21–30, 2016. Publisher Full Text | Google Scholar
  157. F. Gruber, C. M. Ornelas, S. Karner et al., “Nrf2 deficiency causes lipid oxidation, inflammation, and matrix-protease expression in DHA-supplemented and UVA-irradiated skin fibroblasts,” Free Radical Biology & Medicine, vol. 88, pp. 439–451, 2015. Publisher Full Text | Google Scholar
  158. H. Bang, S. Park, S. Saeidi, H. Na, and Y. Surh, “Docosahexaenoic Acid Induces Expression of Heme Oxygenase-1 and NAD(P)H:quinone Oxidoreductase through Activation of Nrf2 in Human Mammary Epithelial Cells,” Molecules, vol. 22, no. 6, p. 969, 2017. Publisher Full Text | Google Scholar
  159. L. M. Chapman, J. A. Roling, L. K. Bingham, M. R. Herald, and W. S. Baldwin, “Construction of a subtractive library from hexavalent chromium treated winter flounder (Pseudopleuronectes americanus) reveals alterations in non-selenium glutathione peroxidases,” Aquatic Toxicology, vol. 67, no. 2, pp. 181–194, 2004. Publisher Full Text | Google Scholar
  160. R. C. Kaltreider, C. A. Pesce, M. A. Ihnat, J. P. Lariviere, and J. W. Hamilton, “Differential effects of arsenic(III) and chromium(VI) on nuclear transcription factor binding,” Molecular Carcinogenesis, vol. 25, no. 3, pp. 219–229, 1999. PubMed Abstract | Publisher Full Text | Google Scholar
  161. C. Risso-de Faverney, N. Orsini, G. de Sousa, and R. Rahmani, “Cadmium-induced apoptosis through the mitochondrial pathway in rainbow trout hepatocytes: involvement of oxidative stress,” Aquatic Toxicology, vol. 69, no. 3, pp. 247–258, 2004. Publisher Full Text | Google Scholar
  162. L. R. Bacanskas, J. Whitaker, and R. T. Di Giulio, “Oxidative stress in two populations of killifish (Fundulus heteroclitus) with differing contaminant exposure histories,” Marine Environmental Research, vol. 58, no. 2–5, pp. 597–601, 2004. Publisher Full Text | Google Scholar
  163. J. N. Meyer, J. D. Smith, G. W. Winston, and R. T. Di Giulio, “Antioxidant defenses in killifish (Fundulus heteroclitus) exposed to contaminated sediments and model prooxidants: short-term and heritable responses,” Aquatic Toxicology, vol. 65, no. 4, pp. 377–395, 2003. Publisher Full Text | Google Scholar
  164. T. D. Gilmore, “The Re1/NF-kappa B/I kappa B signal transduction pathway and cancer.,” Cancer Treatment and Research, vol. 115, pp. 241–265, 2003. PubMed Abstract
  165. U. Hazan, D. Thomas, J. Alcami et al., “Stimulation of a human T-cell clone with anti-CD3 or tumor necrosis factor induces NF-kappa B translocation but not human immunodeficiency virus 1 enhancer-dependent transcription.,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 87, no. 20, pp. 7861–7865, 1990. Publisher Full Text | Google Scholar
  166. X. Shi, V. Castranova, V. Vallyathan, and W. G. Perry, Molecular Mechanisms of Metal Toxicity and Carcinogenesis, Springer US, Boston, MA, 2001.
  167. S. Kim, S. Song, S. Kim et al., “Celecoxib induces apoptosis in cervical cancer cells independent of cyclooxygenase using NF-?B as a possible target,” Journal of Cancer Research and Clinical Oncology, vol. 130, no. 9, 2004. Publisher Full Text | Google Scholar
  168. Y. S. Kim, J. S. Kim, H. C. Jung, and I. S. Song, “The effects of thalidomide on the stimulation of NF-κB activity and TNF-α production by lipopolysaccharide in a human colonic epithelial cell line,” Molecules and Cells, vol. 17, no. 2, pp. 210–216, 2004. PubMed Abstract
  169. M. Westendorp, V. Shatrov, K. Schulze-Osthoff et al., “HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state.,” EMBO Journal, vol. 14, no. 3, pp. 546–554, 1995. Publisher Full Text | Google Scholar
  170. J. Ye, X. Zhang, H. A. Young, Y. Mao, and X. Shi, “Chromium(VI)-induced nuclear factor-кB activation in intact cells via free radical reactions,” Carcinogenesis, vol. 16, no. 10, pp. 2401–2405, 1995. Publisher Full Text | Google Scholar
  171. S. Panda, M. P. Antoch, B. H. Miller et al., “Coordinated transcription of key pathways in the mouse by the circadian clock,” Cell, vol. 109, no. 3, pp. 307–320, 2002. Publisher Full Text | Google Scholar
  172. D. G. Munroe, “Novel intracellular signaling function of prostaglandin H synthase-1 in NF-kB activation,” J Inflammation, vol. 45, pp. 260–268, 1995.
  173. T. D. Gilmore, Ed., Rel/NF-kB. Seminars in Cancer Biology, vol. 8, Academic Press, Cambridge, England, 1997.
  174. K. Lieb et al., “Interleukin-1 beta and tumor necrosis facor-alpha induce expression of alpha 1-antichymotrypsin in human astrocytoma cell by activation of nuclear factor-kappa B,” J Neurochem, vol. 67, no. 5, pp. 2039–2044, 1996.
  175. C. H. Lang, G. J. Nystrom, and R. A. Frost, “Regulation of IGF binding protein-1 in Hep G2 cells by cytokines and reactive oxygen species,” American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 276, no. 3, pp. G719–G727, 1999. PubMed Abstract | Publisher Full Text | Google Scholar
  176. K.-S. Yao and P. J. O'Dwyer, “Involvement of NF-κB in the induction of NAD(P)H: Quinone oxidoreductase (DT-diaphorase) by hypoxia, oltipraz and mitomycin C,” Biochemical Pharmacology, vol. 49, no. 3, pp. 275–282, 1995. PubMed Abstract | Publisher Full Text | Google Scholar
  177. K. Yamamoto, T. Arakawa, N. Ueda, and S. Yamamoto, “Transcriptional roles of nuclear factor κB and nuclear factor-interleukin-6 in the tumor necrosis factor α-dependent induction of cyclooxygenase-2 in MC3T3-E1 cells,” The Journal of Biological Chemistry, vol. 270, no. 52, pp. 31315–31320, 1995. Publisher Full Text | Google Scholar
  178. G. Zhang, C. Slaughter, and E. H. Humphries, “v-rel Induces ectopic expression of an adhesion molecule, DM-GRASP, during B-lymphoma development.,” Molecular and Cellular Biology, vol. 15, no. 3, pp. 1806–1816, 1995. Publisher Full Text | Google Scholar
  179. A. I. Rojo et al., “Regulation of Cu/Zn-superoxide dismutase expression via the phosphatidylinositol 3 kinase/Akt pathway and nuclear factor-kB,” J Neurosci, vol. 24, pp. 9324–9334, 2004.
  180. K. C. Das, Y. Lewis-Molock, and C. W. White, “Activation of NF-kappa B and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 269, no. 5, pp. L588–L602, 1995. Publisher Full Text | Google Scholar
  181. H. Morii, M. Ozaki, and Y. Watanabe, “5′-Flanking Region Surrounding a Human Cytosolic Phospholipase A2 Gene,” Biochemical and Biophysical Research Communications, vol. 205, no. 1, pp. 6–11, 1994. Publisher Full Text | Google Scholar
  182. M. Magnani, R. Crinelli, M. Bianchi, and A. Antonelli, “The ubiquitin-dependent proteolytic system and other potential targets for the modulation of nuclear factor-kB (NF-kB),” Current Drug Targets, vol. 1, no. 4, pp. 387–399, 2000. Publisher Full Text | Google Scholar
  183. C. Y. Ito, A. G. Kazantsev, and A. S. Baldwin, “Three NF-χB sites in the IχB-α promoter are required for induction of gene expression by TNFα,” Nucleic Acids Research, vol. 22, no. 18, pp. 3787–3792, 1994. Publisher Full Text | Google Scholar
  184. S.-C. Sun, P. A. Ganchi, D. W. Ballard, and W. C. Greene, “NF-κB controls expression of inhibitor IκBα: evidence for an inducible autoregulatory pathway,” Science, vol. 259, no. 5103, pp. 1912–1915, 1993. Publisher Full Text | Google Scholar
  185. A. Oeckinghaus and S. Ghosh, “The NF-kappaB family of transcription factors and its regulation,” Cold Spring Harbor Perspectives in Biology, vol. 1, no. 4, Article ID a000034, 2009. Publisher Full Text | Google Scholar
  186. S. Fujioka, J. Niu, C. Schmidt et al., “NF-κB and AP-1 connection: Mechanism of NF-κB-dependent regulation of AP-1 activity,” Molecular and Cellular Biology, vol. 24, no. 17, pp. 7806–7819, 2004. Publisher Full Text | Google Scholar
  187. C. K. Sen and L. Packer, “Antioxidant and redox regulation of gene transcription,” The FASEB Journal, vol. 10, no. 7, pp. 709–720, 1996. Publisher Full Text | Google Scholar
  188. L. E. Otterbein and A. M. Choi, “The Saga of Leucine Zippers Continues,” American Journal of Respiratory Cell and Molecular Biology, vol. 26, no. 2, pp. 161–163, 2002. Publisher Full Text | Google Scholar
  189. T. Prestera, P. Talalay, J. Alam, Y. I. Ahn, P. J. Lee, and A. M. Choi, “Parallel Induction of Heme Oxygenase-1 and Chemoprotective Phase 2 Enzymes by Electrophiles and Antioxidants: Regulation by Upstream Antioxidant-Responsive Elements (ARE),” Molecular Medicine, vol. 1, no. 7, pp. 827–837, 1995. Publisher Full Text | Google Scholar
  190. T. H. Rushmore, M. R. Morton, and C. B. Pickett, “The antioxidant responsive element: activation by oxidative stress and identification of the DNA consensus sequence required for functional activity,” The Journal of Biological Chemistry, vol. 266, no. 18, pp. 11632–11639, 1991.
  191. P. J. Lee and A. M. K. Choi, Serial review: Role of reactive oxygen and nitrogen species (ROS/RNS) in lung injury and diseases. Free Radic Biol Med, vol. 35, Serial review, Role of reactive oxygen and nitrogen species (ROS/RNS) in lung injury and diseases. Free Radic Biol Med, 2003.
  192. M. McMahon, K. Itoh, M. Yamamoto et al., “The cap ‘n’ collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes,” Cancer Research, vol. 61, no. 8, pp. 3299–3307, 2001.
  193. K. Itoh, N. Wakabayashi, Y. Katoh et al., “Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain,” Genes & Development, vol. 13, no. 1, pp. 76–86, 1999. Publisher Full Text | Google Scholar
  194. T. Nguyen, P. Nioi, and C. B. Pickett, “The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress,” The Journal of Biological Chemistry, vol. 284, no. 20, pp. 13291–13295, 2009. Publisher Full Text | Google Scholar
  195. A. Raghunath, K. Sundarraj, R. Nagarajan et al., “Antioxidant response elements: Discovery, classes, regulation and potential applications,” Redox Biology, vol. 17, pp. 297–314, 2018. Publisher Full Text | Google Scholar
  196. K. Chan and Y. W. Kan, “Nrf2 is essential for protection against acute pulmonary injury in mice,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 96, no. 22, pp. 12731–12736, 1999. Publisher Full Text | Google Scholar
  197. T. Ishii, K. Itoh, S. Takahashi et al., “Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages,” The Journal of Biological Chemistry, vol. 275, no. 21, pp. 16023–16029, 2000. Publisher Full Text | Google Scholar
  198. J. D. Hayes, S. A. Chanas, C. Henderson et al., “The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin,” Biochemical Society Transactions, vol. 28, no. 2, pp. 33–41, 2000. Publisher Full Text | Google Scholar
  199. M. Yueh and R. H. Tukey, “ Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice ,” The Journal of Biological Chemistry, vol. 282, no. 12, pp. 8749–8758, 2007. Publisher Full Text | Google Scholar
  200. J. M. Maher, M. Z. Dieter, L. M. Aleksunes et al., “Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway,” Hepatology, vol. 46, no. 5, pp. 1597–1610, 2007. Publisher Full Text | Google Scholar
  201. C. D. Fisher, L. M. Augustine, J. M. Maher et al., “Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2,” Drug Metabolism and Disposition, vol. 35, no. 6, pp. 995–1000, 2007. PubMed Abstract | Publisher Full Text | Google Scholar
  202. J. S. Petrick and C. D. Klaassen, “Importance of hepatic induction of constitutive androstane receptor and other transcription factors that regulate xenobiotic metabolism and transport,” Drug Metabolism and Disposition, vol. 35, no. 10, pp. 1806–1815, 2007. PubMed Abstract | Publisher Full Text | Google Scholar
  203. J. P. Rooney, K. Oshida, R. Kumar, W. S. Baldwin, and J. C. Corton, “Chemical Activation of the Constitutive Androstane Receptor Leads to Activation of Oxidant-Induced Nrf2,” Toxicological Sciences, vol. 167, no. 1, pp. 172–189, 2019. Publisher Full Text | Google Scholar
  204. K. Chan, X.-D. Han, and Y. W. Kan, “An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen,” Proceedings of the National Acadamy of Sciences of the United States of America, vol. 98, no. 8, pp. 4611–4616, 2001. Publisher Full Text | Google Scholar
  205. L. Gao et al., “Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between,” J Biol Chem, vol. 282, no. 4, pp. 2529–2537, 2007.
  206. Sandro Satta, Ayman M. Mahmoud, Fiona L. Wilkinson, M. Yvonne Alexander, and Stephen J. White, “The Role of Nrf2 in Cardiovascular Function and Disease,” Oxidative Medicine and Cellular Longevity, vol. 2017, Article ID 9237263, 18 pages, 2017. Publisher Full Text | Google Scholar
  207. P. J. Meakin, S. Chowdhry, R. S. Sharma et al., “Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance,” Molecular and Cellular Biology, vol. 34, no. 17, pp. 3305–3320, 2014. Publisher Full Text | Google Scholar
  208. A. Uruno, Y. Furusawa, Y. Yagishita et al., “The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus,” Molecular and Cellular Biology, vol. 33, no. 15, pp. 2996–3010, 2013. Publisher Full Text | Google Scholar
  209. S. Vomund, A. Schäfer, M. Parnham, B. Brüne, and A. von Knethen, “Nrf2, the master regulator of anti-oxidative responses,” International Journal of Molecular Sciences, vol. 18, no. 12, article 2772, 2017. Publisher Full Text | Google Scholar
  210. Q. Wang, “Paraquat and MPTP induce neurodegeneration and alteration in the expression profile of microRNAs: the role of transcription factor Nrf2,” NP J Parkinsons, vol. 3, p. 31, 2017. Publisher Full Text | Google Scholar
  211. R. Heuchel, F. Radtke, O. Georgiev, G. Stark, M. Aguet, and W. Schaffner, “The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression,” EMBO Journal, vol. 13, no. 12, pp. 2870–2875, 1994. PubMed Abstract | Publisher Full Text | Google Scholar
  212. L. Xie and P. L. Klerks, “Metallothionein-Like Protein in the Least Killifish heterandria Formosa and its Role in Cadmium Resistance,” Environmental Toxicology and Chemistry, vol. 23, no. 1, p. 173, 2004. Publisher Full Text | Google Scholar
  213. M. Satoh, “Enhanced renal toxicity by inorganic mercury in metallothionein-null mice,” J Pharmacol Exp Ther, vol. 283, no. 3, pp. 1529–1533, 1997.
  214. T. P. Dalton, Q. Li, D. Bittel, L. Liang, and G. K. Andrews, “Oxidative Stress Activates Metal-responsive Transcription Factor-1 Binding Activity,” The Journal of Biological Chemistry, vol. 271, no. 42, pp. 26233–26241, 1996. Publisher Full Text | Google Scholar
  215. C. H. Yan and K. M. Chan, “Cloning of zebrafish metallothionein gene and characterization of its gene promoter region in HepG2 cell line,” Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, vol. 1679, no. 1, pp. 47–58, 2004. Publisher Full Text | Google Scholar
  216. Y. Wang, I. Lorenzi, O. Georgiev, and W. Schaffner, “Metal-responsive transcription factor-1 (MTF-1) selects different types of metal response elements at low vs. high zinc concentration,” biological chemistry, vol. 385, no. 7, pp. 623–632, 2004. PubMed Abstract | Publisher Full Text | Google Scholar
  217. P. J. Daniels, “Mammalian metal response element-binding transcription factor-1 functions as a zinc sensor in yeast, but not as a sensor of cadmium or oxidative stress,” Nucleic Acids Research, vol. 30, no. 14, pp. 3130–3140. Publisher Full Text | Google Scholar
  218. A. P. Cheung, T. H. Lam, and K. M. Chan, “Regulation of Tilapia metallothionein gene expression by heavy metal ions,” Marine Environmental Research, vol. 58, no. 2-5, pp. 389–394, 2004. Publisher Full Text | Google Scholar
  219. J. Asselman, S. Glaholt, Z. Smith et al., “Functional characterization of four metallothionein genes in Daphnia pulex exposed to environmental stressors,” Aquatic Toxicology, vol. 110-111, pp. 54–65, 2012. Publisher Full Text | Google Scholar
  220. J. A. Roling, L. J. Bain, and W. S. Baldwin, “Differential gene expression in mummichogs (Fundulus heteroclitus) following treatment with pyrene: comparison to a creosote contaminated site,” Marine Environmental Research, vol. 57, no. 5, pp. 377–395, 2004. Publisher Full Text | Google Scholar
  221. M. E. Hahn, “Aryl hydrocarbon receptors: diversity and evolution,” Chem Biol Interact, vol. 141, pp. 131–160, 2002. Publisher Full Text | Google Scholar
  222. K. Oshida, N. Vasani, C. Jones et al., “Identification of Chemical Modulators of the Constitutive Activated Receptor (CAR) in a Gene Expression Compendium,” Nuclear Receptor Signaling , vol. 13, no. 1, p. nrs.13002, 2018. Publisher Full Text | Google Scholar
  223. W. S. Baldwin, J. A. Roling, S. Peterson, and L. M. Chapman, “Effects of nonylphenol on hepatic testosterone metabolism and the expression of acute phase proteins in winter flounder (Pleuronectes americanus): Comparison to the effects of Saint John's Wort,” Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, vol. 140, no. 1, pp. 87–96, 2005. Publisher Full Text | Google Scholar
  224. P. Espandiari, V. A. Thomas, H. P. Glauert, M. O'brien, D. Noonan, and L. W. Robertson, “The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) is a peroxisome proliferator in rats,” Toxicological Sciences, vol. 26, no. 1, pp. 85–90, 1995. Publisher Full Text | Google Scholar
  225. M. Thomas, C. Bayha, S. Vetter et al., “ Activating and Inhibitory Functions of WNT/ β -Catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells ,” Molecular Pharmacology, vol. 87, no. 6, pp. 1013–1020, 2015. Publisher Full Text | Google Scholar
  226. R. White, S. Jobling, S. A. Hoare, J. P. Sumpter, and M. G. Parker, “Environmentally persistent alkylphenolic compounds are estrogenic.,” Endocrinology, vol. 135, no. 1, pp. 175–182, 1994. Publisher Full Text | Google Scholar
  227. N. J. Bigley, “Complexity of interferon-γ interactions with HSV-1,” Frontiers in Immunology, vol. 5, no. 11, p. 1, 2014.
  228. N. Nagahora, H. Yamada, S. Kikuchi, M. Hakozaki, and A. Yano, “Nrf2 activation by 5-lipoxygenase metabolites in human umbilical vascular endothelial cells,” Nutrients, vol. 9, no. 9, article no. 1001, 2017. PubMed Abstract | Publisher Full Text | Google Scholar
  229. J. Staudinger, Y. Liu, A. Madan, S. Habeebu, and C. D. Klaassen, “Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor,” Drug Metabolism and Disposition, vol. 29, no. 11, pp. 1467–1472, 2001. PubMed Abstract
Review Article
Nuclear Receptor Research
Vol. 6 (2019), Article ID 101447, 17 pages
doi:10.32527/2019/101447

Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors As a First Step in Protection from Xenobiotics

William S. Baldwin

Clemson University, Biological Sciences/Environmental Toxicology, 132 Long Hall, Clemson, SC 29634, USA

Received 20 November 2019; Accepted 2 October 2019

Editors: Manuel Vazquez Carrera and Pallavi R. Devchand

This article is part of a thematic issue titled “Lipid and Xenobiotic Signaling at the Nucleus
Lead Guest Editor: Pallavi R. Devchand
Guest Editors: Manuel Vazquez Carrera and Simon A. Hirota

Copyright © 2019 William S. Baldwin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

William S. Baldwin, "Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors As a First Step in Protection from Xenobiotics," Nuclear Receptor Research, Vol. 6, Article ID 101447, 17 pages, 2019. doi:10.32527/2019/101447

Review Article
Nuclear Receptor Research
Vol. 6 (2019), Article ID 101447, 17 pages
doi:10.32527/2019/101447

Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors As a First Step in Protection from Xenobiotics

William S. Baldwin

Clemson University, Biological Sciences/Environmental Toxicology, 132 Long Hall, Clemson, SC 29634, USA

Received 20 November 2019; Accepted 2 October 2019

Editors: Manuel Vazquez Carrera and Pallavi R. Devchand

This article is part of a thematic issue titled “Lipid and Xenobiotic Signaling at the Nucleus
Lead Guest Editor: Pallavi R. Devchand
Guest Editors: Manuel Vazquez Carrera and Simon A. Hirota

Copyright © 2019 William S. Baldwin. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite this article

This mini-review examines the crucial importance of transcription factors as a first line of defense in the detoxication of xenobiotics. Key transcription factors that recognize xenobiotics or xenobiotic-induced stress such as reactive oxygen species (ROS), include AhR, PXR, CAR, MTF, Nrf2, NF-κB, and AP-1. These transcription factors constitute a significant portion of the pathways induced by toxicants as they regulate phase I-III detoxication enzymes and transporters as well as other protective proteins such as heat shock proteins, chaperones, and anti-oxidants. Because they are often the first line of defense and induce phase I-III metabolism, could these transcription factors be considered the phase 0 of xenobiotic response?