Science (New York, N.Y.) · 2002
Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR.
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Zhang Jun, Huang Wendong, Chua Steven S, Wei Ping, Moore David D
Аннотация
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.
Предметные рубрики MeSH
AcetaminophenAcetylcysteineAlanine TransaminaseAnalgesics, Non-NarcoticAndrostanolsAnimalsAryl Hydrocarbon HydroxylasesBenzoquinonesConstitutive Androstane ReceptorCytochrome P-450 CYP1A2Cytochrome P-450 CYP2E1Cytochrome P-450 CYP3ACytochrome P-450 Enzyme SystemGlutathioneGlutathione S-Transferase piGlutathione TransferaseHumansIminesIsoenzymesLiverMiceMice, KnockoutMice, TransgenicOxidoreductases, N-DemethylatingPhenobarbitalPyridinesRNA, MessengerReceptors, Cytoplasmic and NuclearTime FactorsTranscription Factors