Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR
- PMID: 12376703
- DOI: 10.1126/science.1073502
Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR
Abstract
We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR null mice, and the CAR null mice were resistant to acetaminophen toxicity. Inhibition of CAR activity by administration of the inverse agonist ligand androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild type but not in CAR null mice. These results suggest an innovative therapeutic approach for treating the adverse effects of acetaminophen and potentially other hepatotoxic agents.
Comment in
-
Toxicology. Protecting liver from painkiller's lethal dose.Science. 2002 Oct 11;298(5592):341-2. doi: 10.1126/science.298.5592.341a. Science. 2002. PMID: 12376675 No abstract available.
Similar articles
-
Toxicology. Protecting liver from painkiller's lethal dose.Science. 2002 Oct 11;298(5592):341-2. doi: 10.1126/science.298.5592.341a. Science. 2002. PMID: 12376675 No abstract available.
-
Role of the nuclear receptor pregnane X receptor in acetaminophen hepatotoxicity.Drug Metab Dispos. 2005 Dec;33(12):1827-36. doi: 10.1124/dmd.105.005256. Epub 2005 Sep 1. Drug Metab Dispos. 2005. PMID: 16141365
-
Characterization of activating signal cointegrator-2 as a novel transcriptional coactivator of the xenobiotic nuclear receptor constitutive androstane receptor.Mol Endocrinol. 2005 Jul;19(7):1711-9. doi: 10.1210/me.2005-0066. Epub 2005 Mar 10. Mol Endocrinol. 2005. PMID: 15764585
-
Alcohol-mediated increases in acetaminophen hepatotoxicity: role of CYP2E and CYP3A.Biochem Pharmacol. 1998 May 15;55(10):1557-65. doi: 10.1016/s0006-2952(97)00656-4. Biochem Pharmacol. 1998. PMID: 9633991 Review.
-
Effects of disease on expression and regulation of CYPs.Mol Aspects Med. 1999 Feb-Apr;20(1-2):55-70, 137. Mol Aspects Med. 1999. PMID: 10575652 Review. No abstract available.
Cited by
-
Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR.PLoS One. 2016 Jul 19;11(7):e0159552. doi: 10.1371/journal.pone.0159552. eCollection 2016. PLoS One. 2016. PMID: 27434302 Free PMC article.
-
Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells.Biochem Pharmacol. 2015 Nov 1;98(1):190-202. doi: 10.1016/j.bcp.2015.08.087. Epub 2015 Aug 12. Biochem Pharmacol. 2015. PMID: 26275810 Free PMC article.
-
Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models.Drug Metab Rev. 2011 Feb;43(1):27-40. doi: 10.3109/03602532.2010.512294. Epub 2010 Sep 21. Drug Metab Rev. 2011. PMID: 20854191 Free PMC article. Review.
-
Adenovirus mediated overexpression of CYP2E1 increases sensitivity of HepG2 cells to acetaminophen induced cytotoxicity.Mol Cell Biochem. 2004 Jul;262(1-2):165-76. doi: 10.1023/b:mcbi.0000038232.61760.9e. Mol Cell Biochem. 2004. PMID: 15532721
-
Pregnane X receptor promotes ethanol-induced hepatosteatosis in mice.J Biol Chem. 2018 Jan 5;293(1):1-17. doi: 10.1074/jbc.M117.815217. Epub 2017 Nov 9. J Biol Chem. 2018. PMID: 29123032 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials
Miscellaneous