藥化lesson 2-藥物毒性的化學(xué)機(jī)制

藥物毒性的化學(xué)機(jī)制1.《創(chuàng)新藥物化學(xué)》(法)卡米爾.喬治.維爾穆特2.ElucidatingMechanismsofdrug-inducedtoxicity.Nature,2005,410.

2Background

1.Almost500yearsago,Paracelsusacknowledgedthatdrugorpoisonisdose-dependent.2.Twenty-century,anexaggeratedpharmacologicalresponseatthetarget.SuchaneffectwouldbeexpectedwitheitheranoverdoseorimpairedMETABOLISMoftheparentdrugs.3.‘Metabolicactivation’ofdrugsandotherchemicals,whichresultsfromtheconversionofparentcompoundsintoproductswithmoreactivity.valproicacid:livertoxicity;anaesthetics:liverinjury4.Covalentbindingtheory:thecovalentbindingofdrugstoproteinsisafactorcontributingtodrugtoxicity.3PrinciplesofreactivechemicalsThereactionofanelectrophileandanucleophileyieldsacovalentbond,whichisgenerallyirreversible(unlesstheproductisintrinsicallyunstable—anester,forexample).Free-radicalpropagationisthebasiceventinvolvedinlipidperoxidationandalsointheproductionofradicalsinDNAandproteins,eventsthatcanhaveavarietyofdetrimentaleffects.?Thebasicreactionsinvolvesimplechemistry—forexample,reactionsofelectrophileswithnucleophilesandfree-radicalpropagation.?Thefirstmetabolicproductorthemostobviouschemicalprospectmightnotbethereactant.?Thestabilityofreactiveproductsinfluencessiteandpatternsofdamage.Ashorthalf-lifetime(t1/2=1s)mightbeconsiderableinacell,andsomereactivemoleculesarelong-lived(t1/2ofmintoh).?Invitrosystemsaremodels,goodforelucidatingdetails.However,onlysomeresults,butnotall,applyinvivo.?Thedoseisanissue,ormoreproperlytheissue,aconceptthatcanbetracedtoParacelsus.?Covalentbindingcanbeanindexoftoxicity,butexceptionsexistevenafterconsiderationsofdose.Otherissues(inadditiontocovalentbinding)arereceptor-mediatedevents(especiallysignalling),abilitytorepairDNAandproteindamage,cellproliferationandimmuneresponses4Whatdowemeanbytoxicity?Accordingtothepathologicaleffectinduced,Toxicitydividedinto4categories

1.Celldeath/tissueinjury:Tissueinjurywasbasedontheobservablepathology,butestablishingexactlyhowthedeathofcertaincellsisrelatedtothetissueinjuryisoftennotobvious2.Alteredphenotype/function:a‘sub-lethal’responseinacell—evenifacelldoesnotdie,suchalterationscancausemajorproblems3.Immunologicalhypersensitivity:aspecialinstanceofanalteredphenotype/function.Itisclearthatsomechemicalscandown-regulateimmunesystemfunctionor,alternatively,functionashaptens(perhapsaftermetabolismandbinding)orevenproduceautoimmunitytonativeproteins.4.Cancer:atypeoftoxicphenotypeandisgenerallyconsideredtoinvolvebothgenotoxicityandothernon-DNAaspectsofcelldeath/tissueinjuryand,insomecases,alteredphenotype/function.productsChemicalInteractionwithreceptorDe-toxitaionreactiveproductsDNAadductsmutation,blockpolymerizationAdductswithSmallmolecules(GSH)DirectdamageeffectSmallamountprotectiveTriggerregulatorysystemsDepleteoxidativedefenceLargeramountHighamountOverwhelm:getoxidativedamagetoproteinsapoptosisNecrosis

Proteinadducts(－)effect(＋)effectLosecrucialfunctionActivatesystemstoyielddetrimentationresponsemetabolismSomeeventsassociatedwiththetoxicityofdrugsandxenobiotics6MechanismsandcontextsofdrugtoxicityMajordrugtoxicitiescanbegroupedintofivecategoriesintermsofthemechanismunderlyingtoxicity:Ontarget,ormechanism-related,toxicity;Hypersensitivityandrelatedimmunologicalreactions;Offtargetpharmacology;Biologicalactivationtototoxicmetabolites;IdiosyncratictoxicitiesStatintoxicity:Muscletoxicity;proteinuriaandkidneyfailureStatinsgenerallyverygoodsafetyrecordintermsoftheirverywidespreaduse.TheirmajormechanismofactionisinhibitionofhydroxymethylglutarylcoenzymeA(HMG-CoA)reductaseintheliver,akeyenzymeinvolvedinthesynthesisofcholesterolandotherproductsoftheisoprenoidpathway.Mechanism:Thesetoxicitiescanberelatedtothedirectactionofthedrugonthesametargetenzymeinthe‘wrong’cell.Inprinciple,thesetoxicitiescanbeavoidedwithlowerdoses,assumingthatefficacyisstillmaintained.Cerivastatin(西立伐他汀)

waswithdrawnfromthemarketinAugust2001Stretages:MorepotentStatin,lowerthedose.

Cerivastatinmightthereforehavebeenausefuldrugatlowerdoses.Insituationsofthistype,onestrategyistoutilizetransportsystemsthatselectivelydeliverthedrugtothetargetcell—forexample,theorganicaniontransporter1B1(OATB)inthecaseofsomestatins.ExamplesExamplesRofecoxib(羅非昔布),

acyclooxygenase2(COX2)inhibitorwithdrawnfromthemarketin2004.Increasedheartdeath.Mechanisms

Rofecoxib,canbereadilyoxidizednonenzymaticallytoformareactivemaleimide,whichindicatesapossiblecovalent-bindingexplanationfortheobservedtoxicity.Inhibitionofprostacyclinsynthesisleadstolackofprotectionfromthromboxanes.TherearethereforeseveralviewsaboutrofecoxibandotherCOX2inhibitorsthatwillneedresolution,andinterpretationwillbeachallengeinlightoftheslighti