Orphan Nuclear Receptors: The Exotics of Xenobiotics

Abstract

nuclear receptor constitutive androstane receptor cytochrome P450 phenobarbital pregnenolone 16α-carbonitrile pregnane X receptor rifampicin steroid and xenobiotic receptor 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene retinoid X receptor Orphan nuclear receptors (NRs)1 include gene products that are structurally related to nuclear hormone receptors but lack known physiological ligands. It has become clear that orphan NRs represent a unique and pivotal resource to uncover new regulatory systems that impact both health and human diseases. In addition to production and clearance of endogenous hormones, mammals also confront numerous foreign chemicals (xenobiotics) such as ingested food, environmental pollutants, and carcinogens as well as prescription and non-prescription drugs. Such compounds may accumulate to toxic levels unless they are metabolized and eliminated, a process largely mediated by the supergene family of cytochrome P450 (CYP) enzymes. Expressed mainly in the liver and capable of recognizing an amazing diversity of xenobiotics, CYP enzymes catalyze the metabolic conversion of xenobiotics to polar derivatives that are more readily eliminated (for reviews, see Refs. 1Gonzalez F.J. Trends Pharmacol. Sci. 1992; 13: 346-352Abstract Full Text PDF PubMed Scopus (393) Google Scholar and 2Denison M.S. Whitlock Jr., J.P. J. Biol. Chem. 1995; 270: 18175-18178Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). Thus, CYP enzymes, especially members of the CYP 1–4 families, are crucial for xenobiotic detoxification and survival of organisms (for a review, see Ref. 3Waxman D.J. Arch. Biochem. Biophys. 1999; 369: 11-23Crossref PubMed Scopus (674) Google Scholar). Among CYP enzymes, the CYP3A and -2B isoenzymes are of particular medical significance. For example, the human CYP3A4 enzyme alone is involved in the metabolism of 50–60% of clinical drugs as well as neutraceuticals and herbal medicines (4Maurel P. Ioannides C. Cytochrome P450, Metabolic and Toxicological Aspects. CRC Press, Inc., Boca Raton, FL1996: 241-270Google Scholar). An additional 25–30% of these compounds are metabolized by the CYP2B isoenzymes. The combined metabolic versatility of CYP3A and -2B, coupled with their inducibility by xenobiotic substrates, constitutes a molecular basis for many clinical drug-drug interactions (4Maurel P. Ioannides C. Cytochrome P450, Metabolic and Toxicological Aspects. CRC Press, Inc., Boca Raton, FL1996: 241-270Google Scholar). Compounds that are strong CYP enzyme inducers such as glucocorticoids, phenobarbital (PB), or rifampicin (RIF) can dramatically affect the clearance of any co-consumed drug that is a substrate for the enzyme. Recently, St. Johns wort, a popular herbal remedy for depression, was found to trigger severe adverse drug-drug interactions with oral contraceptives, the HIV protease inhibitor indinavir, and the immunosuppressant cyclosporin as a consequence of activating the CYP3A system (Ref. 5Moore L.B. Goodwin B. Jones S.A. Wisely G.B. Serabjit-Singh C.J. Willson T.M. Collins J.L. Kliewer S.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 7500-7502Crossref PubMed Scopus (885) Google Scholar, and references therein). In 1992, the aryl hydrocarbon receptor was identified as a transcriptional sensor mediating the induction of CYP1A and -1B1 genes by dioxin and a variety of related polycyclic aromatic hydrocarbons (6Ema M. Sogawa K. Watanabe N. Chujoh Y. Matsushita N. Gotoh O. Funae Y. Fujii-Kuriyama Y. Biochem. Biophys. Res. Commun. 1992; 184: 246-253Crossref PubMed Scopus (371) Google Scholar). Aryl hydrocarbon receptor is a member of the basic helix-loop-helix family of transcription factors, and it was presumed that other basic helix-loop-helix proteins might control the CYP3A and -2B gene families. This turned out to be an incorrect assumption, and the molecular basis for induction of CYP3A and -2Bgenes remained largely unknown. A major conceptual challenge in defining the molecular mechanisms for xenobiotic response is thatCYP genes are induced by thousands of natural and synthetic compounds, and yet the inducibility of CYP enzymes shows clear target gene and species specificity. For example, the antibiotic RIF has been shown to be a specific CYP3A inducer in humans and rabbits, whereas pregnenolone 16α-carbonitrile (PCN), an anti-glucocorticoid, is a rodent-specific CYP3A inducer (Ref. 7Barwick J.L. Quattrochi L.C. Mills A.S. Potenza C. Tukey R.H. Guzelian P.S. Mol. Pharmacol. 1996; 50: 10-16PubMed Google Scholar, and references therein). Pharmacologic studies in cultured primary hepatocytes suggest that it is not the structure of CYP3A genes but rather species-specific cellular factor(s) that dictates the profile ofCYP3A inducibility (7Barwick J.L. Quattrochi L.C. Mills A.S. Potenza C. Tukey R.H. Guzelian P.S. Mol. Pharmacol. 1996; 50: 10-16PubMed Google Scholar). In the past 3–4 years, emerging evidence has increasingly pointed to a unique role for orphan NRs in the regulation