Publication Date:
2002-10-12
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Jun -- Huang, Wendong -- Chua, Steven S -- Wei, Ping -- Moore, David D -- R01 DK46546/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2002 Oct 11;298(5592):422-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12376703" target="_blank"〉PubMed〈/a〉
Keywords:
Acetaminophen/metabolism/*toxicity
;
Acetylcysteine/pharmacology
;
Alanine Transaminase/blood
;
Analgesics, Non-Narcotic/metabolism/toxicity
;
Androstanols/pharmacology
;
Animals
;
Aryl Hydrocarbon Hydroxylases/genetics/metabolism
;
Benzoquinones/metabolism
;
Cytochrome P-450 CYP1A2/genetics/metabolism
;
Cytochrome P-450 CYP2E1/genetics/metabolism
;
Cytochrome P-450 CYP3A
;
Cytochrome P-450 Enzyme System/genetics/metabolism
;
Glutathione/metabolism
;
Glutathione S-Transferase pi
;
Glutathione Transferase/genetics/metabolism
;
Humans
;
Imines/metabolism
;
Isoenzymes/genetics/metabolism
;
Liver/*drug effects/*metabolism/pathology
;
Mice
;
Mice, Knockout
;
Mice, Transgenic
;
Oxidoreductases, N-Demethylating/genetics/metabolism
;
Phenobarbital/pharmacology
;
Pyridines/pharmacology
;
RNA, Messenger/genetics/metabolism
;
Receptors, Cytoplasmic and Nuclear/agonists/antagonists &
;
inhibitors/genetics/*metabolism
;
Time Factors
;
Transcription Factors/agonists/antagonists & inhibitors/genetics/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
