Xenobiotic-sensing nuclear receptors involved in drug metabolism: a structural perspective

Abstract

Xenobiotic compounds undergo a critical range of biotransformations performed by the phase I, II, and III drug-metabolizing enzymes. The oxidation, conjugation, and transportation of potentially harmful xenobiotic and endobiotic compounds achieved by these catalytic systems are significantly regulated, at the gene expression level, by members of the nuclear receptor (NR) family of ligand-modulated transcription factors. Activation of NRs by a variety of endo- and exogenous chemicals are elemental to induction and repression of drug-metabolism pathways. The master xenobiotic sensing NRs, the promiscuous pregnane X receptor and less-promiscuous constitutive androstane receptor are crucial to initial ligand recognition, jump-starting the metabolic process. Other receptors, including farnesoid X receptor, vitamin D receptor, hepatocyte nuclear factor 4 alpha, peroxisome proliferator activated receptor, glucocorticoid receptor, liver X receptor, and RAR-related orphan receptor, are not directly linked to promiscuous xenobiotic binding, but clearly play important roles in the modulation of metabolic gene expression. Crystallographic studies of the ligand-binding domains of nine NRs involved in drug metabolism provide key insights into ligand-based and constitutive activity, coregulator recruitment, and gene regulation. Structures of other, noncanonical transcription factors also shed light on secondary, but important, pathways of control. Pharmacological targeting of some of these nuclear and atypical receptors has been instituted as a means to treat metabolic and developmental disorders and provides a future avenue to be explored for other members of the xenobiotic-sensing NRs.

Targeting xenobiotic receptors PXR and CAR in human diseases

“…Xenobiotic receptors such as PXR and CAR have important roles in drug metabolism and drug–drug interactions (DDIs) by regulating the expression of genes encoding drug-metabolizing enzymes and transporters [14,15]. The unique structure of the ligand-binding pocket of PXR enables the pocket to accommodate molecules of various shapes and sizes [14,16].…”

Genome-wide analysis of trans-splicing in the nematode Pristionchus pacificus unravels conserved gene functions for germline and dauer development in divergent operons

“…A similar analysis on the larger set of 389 genes from the 128 operons conserved between all predicted operons across the two species again identified significant overrepresentation of genes and domains involved in detoxification pathways (glutathione Stransferase gene family gst-, UDP-glucuronosyl transferases encoded by the ugt gene family, cytochrome P450 enzymes encoded by the cyp gene family, and P-glycoprotein-related ABC transporters of the pgp gene family; corresponding Pfam domains "GST_N," "GST_C," "UDPGT," and "p450") (Supplemental Table S7), as well as nuclear hormone receptor activity (nhr gene family, Pfam domains "Hormone_recep" and "zf-C4") (Supplemental Table S7). The genes of gst, ugt, and cyp families work together during phase I and phase II metabolism of lipophilic substances such as xenobiotic toxins (Jakoby and Ziegler 1990;Oesch and Arand 1999), and many of the nuclear hormone receptors serve as xenobiotic sensors that can regulate expression of cytochrome P450 enzymes and UDP-glucuronosyl transferases (Zhou et al 2005;Wallace and Redinbo 2013). It is therefore remarkable to see their enrichment within the set of conserved operons and suggests that their concerted coregulation might be one of the adaptive functions of operonic organization and thus retained across the evolutionary time separating P. pacificus and C. elegans.…”

Resveratrol increases hepatic SHBG expression through human constitutive androstane receptor: a new Contribution to the French Paradox

“…The DR-1 element through which CAR appears to mediate the effects of resveratrol on SHBG expression also binds COUP-TF, HNF-4α 8 and PPARγ 9 . It may also bind other members of the PPAR family, as well as RXR homodimers or heterodimers with other NHRs, including RAR, LXR, PPARα, FXR, and PXR many of which are metabolic, drug or xenobiotic sensors 67 . Thus, unlike the DR-1 element positioned close to the SHBG transcription start site, and which functions through interactions with COUP-TF and HNF-4α as the main transcriptional "on-off " switch in the liver 8 , the upstream DR-1 element that interacts with CAR may represent a "fine-tuner" that responds to a number of related NHRs many of which regulate responses to metabolic disturbances during disease or after exposure to drugs or environmental xenobiotic ligands.…”