简介：AIM:ToinvestigatethepreciserolesofCARinCCl4-inducedacutehepatotoxicity.METHODS:Toprepareanacuteliverinjurymodel,CCl4wasintraperitoneallyinjectedinCAR+/+andCAR-/-mice.RESULTS:ElevationofserumalanineaminotransferaseandextensionofcentrilobularnecrosiswereslightlyinhibitedinCAR-/-micecomparedtoCAR+/+micewithoutPB.AdministrationofaCARinducer,PB,revealedthatCCl4-inducedlivertoxicitywaspartiallyinhibitedinCAR-/-micecomparedwithCAR+/+mice.Ontheotherhand,androstanol,aninverseagonistligand,inhibitedhepatotoxicityinCAR+/+butnotinCAR-/-mice.Thus,CARactivationcausedCCl4hepatotoxicitywhileCARinhibitionresultedinpartialprotectionagainstCCl4-inducedhepatotoxicity.TherewerenodifferencesintheexpressionofCYP2E1,themainmetabolizingenzymeforCCl4,betweenCAR+/+andCAR-/-mice.However,theexpressionofotherCCl4-metabolizingenzymes,suchasCYP2B10and3A11,wasinducedbyPBinCAR+/+butnotinCAR-/-mice.AlthoughthemainpathwayofCCl4-inducedacuteliverinjuryismediatedbyCYP2E1,CARmodulatesitspathwayviainductionofCYP2B10and3A11inthepresenceofactivatororinhibitor.CONCLUSION:ThenuclearreceptorCARmodulatesCCl4-inducedliverinjuryviainductionofCCl4-metabolizingenzymesinthepresenceofanactivator.OurresultssuggestthatdrugsinteractingwithnuclearreceptorssuchasPBmightplaycriticalrolesindrug-inducedliverinjuryordrugdruginteractioneventhoughsuchdrugsthemselvesarenothepatotoxic.