Constitutive active/androstane receptor

SXR Steroid end xenobiotics receptor (human] CAR Constitutive active (androstane) receptor other UGT substrates... 

Yamamoto, Y, Moore, R., Goldsworthy, T. L., Negishi, M., and Maronpot, R. R. (2004). The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64, 7197-7200. 

Phillips, J.M., Yamamoto, Y., Negishi, M., Maronpot, R.R. and Goodman, J.I. (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicological Sciences, 96, 72-82. 

Tien, E.S., Matsui, K., Moore, R. and Negishi, M. (2007) The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. The Journal of Pharmacology and Experimental Therapeutics, 320, 307-313. 

Min, G., Kim, H., Bae, Y., Petz, L., and Kemper, J. K. (2002) Inhibitory cross-talk between estrogen receptor (ER) and constitutively activated androstane receptor (CAR). CAR inhibits ER-mediated signaling pathway by squelching pi 60 coactivators.. /. Biol. Chem. Ill, 34626-34633. 

Mutoh S, Sobhany M, Moore R, Perera L, Pedersen L, Sueyoshi T, Negishi M (2013) Phenobarbital indirectly activates the constitutive active androstane receptor (CAR) by inhibition of epidermal growth factor receptor signaling. Sci Signal 6 ra31... 

The constitutive/active androstane receptor CAR, originally named MB67, was first cloned as a nuclear receptor that constitutively activates the retinoic acid response element in cell-based transfection assays [81], Then, from 1998 to 1999, the function of CAR relative to the induction of CRP genes as a phenobarbital activated nuclear receptor was established [7,82,83], Subsequently, the in vivo roles of CAR in induction were confirmed using CAR KO mice [84, 85], One of the major interests of the past half centuiy... 

Osabe M, Negishi M (2011) Active ERKl/2 protein interacts with the phosphorylated nuclear constitutive active/androstane receptor (CAR NR 113), repressing dephosphoiylation and sequestering CAR in the eytoplasm. J Biol Chem 286 35763 35769... 

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. 

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. 

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). 

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