Figure 6: NR-mediated regulation of drug metabolism, drug disposition: control at multiple steps. Transcriptional regulation primarily dictates NR expression and its cellular abundance (box at the upper right corner). Post-translational modification modulates NR stability and NR activity (box at upper left corner). (A) Drugs activate xenobiotic NRs (PXR, CAR), which in turn modulate the expression of phase 0-III mediators via induction of XREs. Ligand-activated VDR also induces DME and transporter expression. (B) Drug-drug, drug-herb, drug-food interactions cause altered NR expression/activity leading to altered expression of DME/transporter. An interfering agent (such as a second drug or a dietary constituent) may also modulate DME/transporter activity via competitive or allosteric regulation. (C) Histone modification and DNA methylation modulate NR expression; they also modulate NR-regulated DME/transporter expression due to epigenetic changes at or near XREs. (D) SNP at an XRE or at an alternate regulatory locus of phase 0-III genes leads to a change in the NR interaction with the response element, which alters DME and transporter expression. SNP in coding regions of PXR/CAR/VDR/HNF4-α, DMEs or transporters can alter the activity or cellular abundance of these proteins/enzymes. (E) Micro RNAs and long non-coding RNAs (lncRNAs) regulate the cellular abundance of NRs and mediators of phase 0-III processes. (F) Interindividual differences in drug response stem from SNP at an XRE, at another NR-interacting regulatory locus of the target gene, or at the coding region of NRs (PXR/CAR/VDR/HNF4-α) or phase 0-III mediators.