Nuclearreceptorsaretranscriptionfactorsthatareactivateduponbindingtoitsligands.Initially,theyhadbeenclassifiedasclassicendocrinenuclearhormonereceptorsandorphanreceptors.However,furtherstudieshaveledtotheidentificationoflipidligandsforsomeofthese‘adopted’orphanreceptors,whichareresponsIBLeforlipidmetabolism,storageorelimination.OneofthecharacteristicsofthesereceptorsisthattheyactbyformingheterodimerswithretinoidXreceptor(RXR).Thereceptorsincludeperoxisomeproliferators-Activatedreceptors(PPARs)forfattyacids,liverXreceptor(LCR)foroxysterols,FarnesoidXreceptors(FXR)forbileacidsandsteroidxenobioticreceptor/Xreceptor(SXR/PXRorNsil2)forxenobiotics.OtherorphanreceptorsalsorequireRXRforitsfunctionsarevitaminDreceptor(VDR)forvitaminDandretinoicacidreceptor(RAR)forretinoidacids,althoughthesereceptorsarenotinvolvedinlipidmetabolism.Uponbindingtovariousligands,threeclassesofproteinsaresynthesizedincludinglipidbindingproteins,theATP-bindingcassette(ABC)transportersandcytochromeP450memberproteinswhichcatalyzeslipidanabolism,metabolismandelimination.Inadditiontolipidmetabolism,somemembersofthecytochromeP450familygenesareresponsibleforactivationofprocarcinogens,detoxificationofenvironmentaltoxinsandmetabolismofdrugsandxenobiotics.Inparticular,CAR,Nsil2andrecentlyidentifiedVDRareimportantinup-regulationofthesecytochromes.OfallthehumancytochromeP450genes,onlyafewCYP1A2,CYP2C9,CYP2C19,CYP2D6,CYP2E1andCYP3A4accountformosttoxicityeffects,specificallyCYP3Aisresponsibleforclearingapproximatelyhalfoftheclinicallyprescribeddrugs.Forinstance,acetaminophen,oneofthemostcommonlyuseddrug,istoxicinhighdosesduetotheactivationofCARandthedrug’ssubsequentconversiontoacetyl-p-benzoquinoneimine(NAPQI)byCYP1A2,CYP2E1andCYP3A.

Contributor:Yen-LiangChen,PhD

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