The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism
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 defence, 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.
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CAR is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.
“The nuclear receptor, constitutive androstane receptor (CAR; NR1I3), is a pleiotropic regulator of liver detoxification, metabolism, proliferation, and hepatomegaly.7, 8, 9, 10, 11, 12, 13, 14”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [8]
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- Authors
- Wei, P., Zhang, J., Egan-Hafley, M., Liang, S., & Moore, D. D.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Moore, David D.
- Venue
- Nature
- Published
- 2000-10
- Volume
- 407
- Issue
- 6806
- Pages
- 920-923
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1485938486
- Cited by
- 654
- References
- 1
- Citations by year
- 2026: 1 · 2025: 11 · 2024: 5 · 2023: 8 · 2022: 21 · 2021: 11 · 2020: 19 · 2019: 16 · 2018: 30 · 2017: 24 · 2016: 33 · 2015: 26 · 2014: 20 · 2013: 27 · 2012: 20
- FWCI
- 26.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Genentech
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- constitutive androstane receptor, xenobiotic induction, cytochrome P450, Cyp2b10, TCPOBOP, liver hypertrophy, liver hyperplasia, drug metabolism, nuclear receptors
- MeSH terms
- Cytochrome P450 Family 2, Alanine Transaminase, Animals, Aryl Hydrocarbon Hydroxylases, Cell Line, Cocaine, Cytochrome P-450 Enzyme System, Pharmaceutical Preparations, Enzyme Induction, Female, Humans, Liver, Male, Phenobarbital, Pyridines, Receptors, Virus, Steroid Hydroxylases, Zoxazolamine, Xenobiotics, Gene Expression Regulation, Enzymologic, Gene Targeting, Mice, Coxsackie and Adenovirus Receptor-Like Membrane Protein
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