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1、药物毒性的化学机制1.《创新药物化学》(法)卡米尔.乔治.维尔穆特2.ElucidatingMechanismsofdrug-inducedtoxicity.Nature,2005,410.2Background1.Almost500yearsago,Paracelsusacknowledgedthatdrugorpoisonisdose-dependent.2.Twenty-century,anexaggeratedpharmacologicalresponseatthetarget.Suchaneffectwouldbeexpectedwitheitheranoverd
2、oseorimpairedMETABOLISMoftheparentdrugs.3.‘Metabolicactivation’ofdrugsandotherchemicals,whichresultsfromtheconversionofparentcompoundsintoproductswithmoreactivity.valproicacid:livertoxicity;anaesthetics:liverinjury4.Covalentbindingtheory:thecovalentbindingofdrugstoproteinsisafactorcontribu
3、tingtodrugtoxicity.3PrinciplesofreactivechemicalsThereactionofanelectrophileandanucleophileyieldsacovalentbond,whichisgenerallyirreversible(unlesstheproductisintrinsicallyunstable—anester,forexample).Free-radicalpropagationisthebasiceventinvolvedinlipidperoxidationandalsointheproductionofr
4、adicalsinDNAandproteins,eventsthatcanhaveavarietyofdetrimentaleffects.•Thebasicreactionsinvolvesimplechemistry—forexample,reactionsofelectrophileswithnucleophilesandfree-radicalpropagation.•Thefirstmetabolicproductorthemostobviouschemicalprospectmightnotbethereactant.•Thestabilityofreactiv
5、eproductsinfluencessiteandpatternsofdamage.Ashorthalf-lifetime(t1/2=1s)mightbeconsiderableinacell,andsomereactivemoleculesarelong-lived(t1/2ofmintoh).•Invitrosystemsaremodels,goodforelucidatingdetails.However,onlysomeresults,butnotall,applyinvivo.•Thedoseisanissue,ormoreproperlytheissue,ac
6、onceptthatcanbetracedtoParacelsus.•Covalentbindingcanbeanindexoftoxicity,butexceptionsexistevenafterconsiderationsofdose.Otherissues(inadditiontocovalentbinding)arereceptor-mediatedevents(especiallysignalling),abilitytorepairDNAandproteindamage,cellproliferationandimmuneresponses4Whatdowem
7、eanbytoxicity?Accordingtothepathologicaleffectinduced,Toxicitydividedinto4categories1.Celldeath/tissueinjury:Tissueinjurywasbasedontheobservablepathology,butestablishingexactlyhowthedeathofcertaincellsisrelatedtothetissueinjuryisoftennotobvious2.Alteredphenoty
