The Nuclear Receptor CAR

Nuclear Receptor Regulation of Hepatic Cytochrome P450 Enzymes. Figure 1 General mechanism for transcriptional activation of CYP genes by xenochemicals that activate their cognate xeno-receptor proteins. In the case of Ah receptor, the receptor s heterodimerization partner is Arnt, whereas in the case of the nuclear receptors CAR, PXR, and PPARa, the heterodimerization partner is RXR. The coactivator and basal transcription factor complexes shown are each comprised of a large number of protein components. 

Sugatani J, Kojima H, Ueda A et al (2001) The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33 1232-1238... 

Forman BM, Tzameli I, Choi HS, et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 1998 395 612-15. 

Tzameli I, Pissios P, Schuetz EG, et al. The xenobiotic compound l,4-6 [2-(3,5-di chloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol Cell Biol 2000 20 2951-58. 

Wei P, Zhang J, Egan-Hafley M, et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabohsm. Nature 2000 407 920-3. 

Kobayashi K, Sueyoshi T, Inoue K, Moore R, Negishi M (2003) Cytoplasmic accumulation of the nuclear receptor CAR by a tetratrico-peptide repeat protein in HepG2 cells. Mol Pharmacol 64(5) 1069-1075. doi 10.1124/ mol.64.5.1069... 

Windshugel, B., Jyrkkarinne, J., Vanamo, J., Poso, A., Honkakoski, P. and Sippl, W. (2007) Comparison of homology models and X-ray structures of the nuclear receptor CAR assessing the structural basis of constitutive activity Journal of Molecular Graphics ej Modelling, 25, 644-657. 

Yoshinari, K., Kobayashi, K., Moore, R., Kawamoto, T. and Negishi, M. (2003) Identification of the nuclear receptor CAR HSP90 complex in mouse liver and recruitment of protein phosphatase 2A in response to phenobarbital. FEBS Letters, 548, 17-20. 

Inoue, K., Borchers, C.H. and Negishi, M. (2006) Cohesin protein SMC1 represses the nuclear receptor CAR-mediated synergistic activation of a human P450 gene by xenobiotics. The Biochemical Journal, 398, 125-133. 

Maglich, J.M., Watson, J., McMillen, P.J., Goodwin, B., Willson, T.M. and Moore, J.T. (2004) The nuclear receptor CAR is a regulator of thyroid hormone metabolism during caloric restriction. The Journal of Biological Chemistry, 279, 19832-19838. 

Kanno, Y., Suzuki, M., Nakahama, T., and Inouye, Y. (2005) Characterization of nuclear localization signals and cytoplasmic retention region in the nuclear receptor CAR. Biochim. Biophys. Acta 1745, 215-222. 

CYP2B6 is detected in human liver and is about 1-2% of total hepatic CYP. The substrates for CYP2B6 include 6-aminochrysene, methoxychlor, NNK, and cyclophosphamide. CYP2B6 in human primary hepatocytes is typically induced by PB and rifampicin through the nuclear receptor CAR (constitu-tively active receptor) (Sueyoshi et al., 1999) and probably also by PXR... 

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