The Constitutive Androstane Receptor

Zhang, J., Huang, W., Qatanani, M., Evans, R.M. and Moore, D.D. (2004) The constitutive androstane receptor and pregnane X receptor function coordinately to prevent bile acid-induced hepatotoxicity. Journal of Biological Chemistry, 279, 49517 19522. 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

Assem M, Schuetz EG, Leggas M, Sun D, Yasuda K, Reid G, Zelcer N, Adachi M, Strom S, Evans RM, Moore DD, Borst P, Schuetz JD. Interactions between hepatic Mrp4 and Sult2A as revealed by the constitutive androstane receptor and Mrp4 knockout mice. J Biol Chem 2004 279 22250-22257. 

Ferguson SS, LeCluyse EL, Negishi M, Goldstein JA. Regulation of human CYP2C9 by the constitutive androstane receptor discovery of a new distal binding site. Mol Pharmacol 2002 62 737-746. 

Induction of CYP-mediated metabolism requires prior exposure of the hepatocyte s CYP-synthesis mechanism to a chemical inducer. The inducer signals the synthetic mechanisms to upregulate the production of one or more CYP isoforms, a process that takes time. Consequently, evidence of increased CYP activity is of slow onset following initiation of exposure to the inducer, and conversely slowly reverts to baseline after the inducer is removed (46,47). Enhancement of CYP expression/activity due to chemical induction therefore reflects prior, but not necessarily current, exposure to the inducer. Nuclear receptors, such as the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), have been identified as key elements in the process of transcriptional activation (48-56). 

Dussault I, Lin M, Hollister K, Wang EH, Synold TW, Forman BM. A structural model of the constitutive androstane receptor defines novel interactions that mediate hgand-independent activity. J Biol Chem 2001 276 33309-12. 

PXR), the Ah receptor (AhR) and the constitutive androstane receptor (CAR) ligand binding domains from the human oestrogen receptor alpha (hERalpha) crystal structure, and the human peroxisome proliferator activated receptor alpha (PPARalpha) ligand binding domain from the human PPARgamma crystal structure. / Steroid Biochem Mol Biol 2003 84 117-32. 

Blizard, D., T. Sueyoshi, M. Negishi, S.S. Dehal and D. Kupfer. Mechanism of induction of cytochrome P450 enzymes by the proestrogenic endocrine disruptin pesticide-methoxychlor interactions of methoxychlor metabolites with the constitutive androstane receptor system. Drug Metab. Dispos. 29 781-785, 2001. 

Treatment with each of the three conazoles resulted in similar histopathologi-cal and clinical chemistry results. A common nongenotoxic mechanism of rodent hepatocarcinogenesis involves the activation of the constitutive androstane receptor (CAR) (see Chapter 16), hepatocyte hypertrophy, the induction of CYP2B, the induction of cell proliferation, and the inhibition of apoptosis has been proposed for conazoles (Chen et al. 2009 Peffer et al. 2007). These alterations were produced by... 

Christoph Handschin describes the role of nuclear receptors, more specifically the pregnane X receptor and the constitutive androstane receptor, in the induction of drug metabolism and detoxification of drugs and other xenobiotics. 

Qatanani, M., Zhang, J., and Moore, D. D. (2005) Role of the constitutive androstane receptor in xenobiotic-induced thyroid hormone metabolism. Endocrinology 146, 995-1002. 

D. D. (2003) Induction of bilirubin clearance by the constitutive androstane receptor. Proc. Natl Acad. Sci. USA 100, 4156-4161. 

Thompson, E. E., Kuttab-Boulos, H., Krasowski, M. D., and Di, R. A. (2005) Functional constraints on the constitutive androstane receptor inferred from human sequence variation and cross-species comparisons. Plum. Genomics 2, 168-178. 

Assem, M., Schuetz, E. G., Leggas, M., Sun, D., Yasuda, K., Reid, G., Zelcer, N., Adachi, M., Strom, S., Evans, R. M., et al. (2004) Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. 

The adaptive response to xenobiotics is orchestrated in the cell by a subset of receptors that act primarily in the nucleus. For this chapter, we will employ a liberal definition of nuclear receptor (NR) that includes all signaling molecules that function as ligand-binding transcription factors that bind to specific DNA enhancer sequences and upregulate the transcription of CYP genes. Two classes of NRs will be discussed in this chapter. Members of the nuclear hormone receptor (NHR) superfamily to be reviewed include the constitutive androstane receptor (CAR), the pregnane X-receptor (PXR), and the peroxisome prolifera-tor activated receptors (PPARs). A single member of the PAS superfamily, the aryl hydrocarbon receptor (AHR), will also be discussed. 

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