Constitutive androstane receptor activation

Cherrington NJ, Hartley DP, Li N, et al. Organ distribution of multidrug resistance proteins 1, 2, and 3 (Mrpl, 2, and 3) mRNA and hepatic induction of Mrp3 by constitutive androstane receptor activators in rats. J Pharmacol Exp Ther 2002 300 97-104. 

Shindo, S., Numazawa, S. andYoshida,T. (2007) A physiological role of AMP-activated protein kinase in phenobarbital-mediated constitutive androstane receptor activation and CYP2B induction. The Biochemical Journal, 401, 735-741. 

CAR (constitutive androstane receptor) activators in humans-3-methylcholanthrene, phenylpropionic acid, phenobarbital, phenytoin, carbamazepine. PPARa (peroxisome proliferated-activated receptor-a) activator in humans-clofibric acid, fenobibric acid, pirinixic acid. 

In addition to PXR, the expression of UGT1A1 and several other UGT isoforms have also been reported to be regulated by several other nuclear receptors, including constitutive androstane receptor (CAR) [25,27,28] and peroxisome proliferator activated receptor a (PPARa) [29,30],... 

Kast, H.R., Goodwin, B., Tarr, P.T., Jones, S.A., Anisfeld, A.M., Stoltz, C.M., Tontonoz, P., Kliewer, S., Willson, T.M. and Edwards, P.A. (2002) Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. Journal of Biological Chemistry, 277, 2908-2915. 

Figure 5.34 Mechanism of induction of CYP2B6 by a chemical such as the drug phenobarbital. This drug activates a nuclear receptor (CAR).This combines with the retinoid X receptor and binds to PBREM, as specific section of the CYP gene, which stimulates the production of CYP2B6 mRNA leading to the production of CYP2B6 protein and enzyme. Abbreviations CAR, constitutive androstane receptor RXR retinoid X receptor PBREM, phenobarbital-responsive enhancer module.

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). 

Abbreviations. AhR, aromatic hydrocarbon receptor TCDD, tetrachlorodibenzodioxin PXR, pregnenolone-16a-nitrile-X-receptor PCN, pregnenolone-16a-nitrile CAR, constitutive androstane receptor MC, methylcholanthrene PPARa, peroxisome proliferated-activated receptor-a FXR, famesoid-X-receptor LXR, liver-X-receptor RXR, retinod-X-receptor 5-HETE, 5-OH-eicosatetraenoic acid LTB4, leukotriene B4 13-HODE, hydroxyoctadecadienoic acid DMXAA, dimethylxan-thenone-4-acetic acid. 

Kast HR, Goodwin B, Tarr PT, et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, famesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem 2002 277 2908-2915. 

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). 

Wyde ME, Kirwan SE, Zhang F, et al. Di-n-butyl phthalate activates constitutive androstane receptor and pregnane X receptor and enhances the expression of steroid-metabolizing enzymes in the liver of rat fetuses. Toxicol Sci 2005 86(2) 281—90. 

Muangmoonchai R, Smirlis D, Wong SC, et al. Xenobiotic induction of cytochrome P450 2B1 (CYP2B1) is mediated by the orphan nuclear receptor constitutive androstane receptor (CAR) and requires steroid co-activator 1 (SRC-1) and the transcription factor Spl. Biochem J 2001 355 71-78. 

Faucette SR, Zhang TC, Moore R, Sueyoshi T, Omiecinski C, LeCluyse EL, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Exp Ther 2007 320 72-80. 

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. 

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