Abstract
Organisms encounter a wide range of foreign compounds—or ‘xenobiotics’—with potentially harmful consequences. The cytochrome P450 (CYP) enzymes metabolize xenobiotics and thus are a primary defence against these compounds. Increased expression of specific CYP genes in response to particular xenobiotics is a central component of this defence1, although such induction can also increase production of toxic metabolites. Here we show that the nuclear receptor CAR mediates the response evoked by a class of xenobiotics known as the ‘phenobarbital-like inducers’. The strong activation of Cyp2b10 gene expression by phenobarbital, or by the more potent TCPOBOP, is absent in mice lacking the CAR gene. These animals also show decreased metabolism of the classic CYP substrate zoxazolamine and a complete loss of the liver hypertrophic and hyperplastic responses to these inducers. Cocaine causes acute hepatotoxicity in wild-type mice previously exposed to phenobarbital-like inducers and this toxicity is also absent in the CAR-deficient animals. Thus, loss of CAR function alters sensitivity to toxins, increasing or decreasing it depending on the compound. Modulation of CAR activity in humans may significantly affect metabolism of drugs and other xenobiotics.
This is a preview of subscription content, access via your institution
Relevant articles
Open Access articles citing this article.
-
Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPARα regulates anaerobic glycolysis
Scientific Reports Open Access 14 March 2017
-
Upregulation of CYP2S1 by oxaliplatin is associated with p53 status in colorectal cancer cell lines
Scientific Reports Open Access 09 September 2016
-
Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells
Scientific Reports Open Access 17 June 2016
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Get just this article for as long as you need it
$39.95
Prices may be subject to local taxes which are calculated during checkout
References
Waxman, D. J. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369, 11–23 (1999).
Poland, A. et al. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene, a potent phenobarbital-like inducer of microsomal monooxygenase activity. Mol. Pharmacol. 18, 571–580 (1980).
Honkakoski, P., Zelko, I., Sueyoshi, T. & Negishi, M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol. Cell. Biol. 18, 5652–5658 (1998).
Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P. & Negishi, M. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274, 6043–6046 (1999).
Tzameli, I., Pissios, P., Schuetz, E. G. & D, Moore, D. D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell. Biol. 20, 2951–2958 (2000).
Jones, S. A. et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 27–39 (2000).
Moore, L. B. et al. Orphan nuclear receptors, constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122–15127 (2000).
Baes, M. et al. A new orphan member of the nuclear receptor superfamily that interacts with a subset of retinoic acid response elements. Mol. Cell. Biol. 14, 1544–1552 ( 1994).
Choi, H. S. et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J. Biol. Chem. 272, 23565–23571 (1997).
Heubel, F., Reuter, T. & Gerstner, E. Differences between induction effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene and phenobarbitone. Biochem. Pharmacol. 38, 1293–1300 (1989).
Carthew, P., Edwards, R. E. & Nolan, B. M. The quantitative distinction of hyperplasia from hypertrophy in hepatomegaly induced in the rat liver by phenobarbital. Toxicol. Sci. 44, 46–51 (1998).
Cunningham, M. L. Role of increased DNA replication in the carcinogenic risk of nonmutagenic chemical carcinogens. Mutat. Res. 365, 59 –69 (1996).
Robinson, J. R. & Nebert, D. W. Genetic expression of aryl hydrocarbon hydroxylase induction. Presence or absence of association with zoxazolamine, diphenylhydantoin, and hexobarbital metabolism. Mol. Pharmacol. 10, 484–493 (1974).
Bornheim, L. M. Effect of cytochrome P450 inducers on cocaine-mediated hepatotoxicity. Toxicol. Appl. Pharmacol. 150, 158– 165 (1998).
Kliewer, S. A. et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73–82 (1998).
Blumberg, B. et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12, 3195–3205 (1998).
Lehmann, J. M. et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016–1023 (1998).
Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).
Shimada, T., Yamazaki, H., Mimura, M., Inui, Y. & Guengerich, F. P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther. 270, 414– 423 (1994).
Code, E. L. et al. Human cytochrome P4502B6: interindividual hepatic expression, substrate specificity, and role in procarcinogen activation. Drug Metab. Dispos. 25, 985–993 (1997).
Selim, K. & Kaplowitz, N. Hepatotoxicity of psychotropic drugs. Hepatology 29, 1347– 1351 (1999).
Liang, H. C. et al. Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism. Proc. Natl Acad. Sci. USA 93, 1671–1676 (1996).
Acknowledgements
This work was supported by a grant from NIH to D.D.M. We thank F. DeMayo for help with generating the knockout animals.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wei, P., Zhang, J., Egan-Hafley, M. et al. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407, 920–923 (2000). https://doi.org/10.1038/35038112
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35038112
This article is cited by
-
CAR directs T cell adaptation to bile acids in the small intestine
Nature (2021)
-
Hepatocyte SHP deficiency protects mice from acetaminophen-evoked liver injury in a JNK-signaling regulation and GADD45β-dependent manner
Archives of Toxicology (2018)
-
Hyper- and hypo- nutrition studies of the hepatic transcriptome and epigenome suggest that PPARα regulates anaerobic glycolysis
Scientific Reports (2017)
-
Impact of Drug Treatment at Neonatal Ages on Variability of Drug Metabolism and Drug-Drug Interactions in Adult Life
Current Pharmacology Reports (2017)
-
Activation of nuclear receptor CAR by an environmental pollutant perfluorooctanoic acid
Archives of Toxicology (2017)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
