药化lesson 2药物毒性的化学机制

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 2 Background 1 Almost500yearsago Paracelsusacknowledgedthatdrugorpoisonisdose dependent 2 Twenty century anexaggeratedpharmacologicalresponseatthetarget SuchaneffectwouldbeexpectedwitheitheranoverdoseorimpairedMETABOLISMoftheparentdrugs 3 Metabolicactivation ofdrugsandotherchemicals whichresultsfromtheconversionofparentcompoundsintoproductswithmoreactivity valproicacid livertoxicity anaesthetics liverinjury 4 Covalentbindingtheory thecovalentbindingofdrugstoproteinsisafactorcontributingtodrugtoxicity 3 Principlesofreactivechemicals Thereactionofanelectrophileandanucleophileyieldsacovalentbond 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 cellproliferationandimmuneresponses 4 Whatdowemeanbytoxicity Accordingtothepathologicaleffectinduced Toxicitydividedinto4categories1 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 products Chemical Interactionwithreceptor De toxitaion reactiveproducts DNAadducts mutation blockpolymerization AdductswithSmallmolecules GSH Directdamageeffect Smallamountprotective Triggerregulatorysystems Depleteoxidativedefence Largeramount Highamount Overwhelm getoxidativedamagetoproteins apoptosis Necrosis Proteinadducts effect effect Losecrucialfunction Activatesystemstoyielddetrimentationresponse metabolism Someeventsassociatedwiththetoxicityofdrugsandxenobiotics 6 Mechanismsandcontextsofdrugtoxicity Majordrugtoxicitiescanbegroupedintofivecategoriesintermsofthemechanismunderlyingtoxicity Ontarget ormechanism related toxicity Hypersensitivityandrelatedimmunologicalreactions Offtargetpharmacology Biologicalactivationtototoxicmetabolites Idiosyncratictoxicities 9 由尿排出 毒性 NAPQI 乙酰氨基酚的代谢 1 乙酰氨基酚的毒性 主要表现为肝毒性 一般认为来自代谢中间体N 乙酰 p 苯醌亚胺 NAPQI NAPQI是细胞成分和吡啶核苷酸的硫羟基的良好氧化剂 10 NAPQI产生的机制 11 NAPQI的氧化 还原循环 NAPQI产生的毒性 12 2 Tienilicacid 替尼酸 的毒性 由尿排出 自身免疫性疾病 免疫性肝炎 毒性 退市 原因是免疫肝炎 利尿药 3 卤代烷的毒性 麻醉药主要 80 由肺排出少量 15 肝代谢肝毒性 由尿排出 消毒 损伤细胞大分子 肝细胞死亡 毒性 还原途径 氧化途径 14 3 卤代烷的毒性 卤烷转变为三氟乙酰氯后与蛋白的结合 毒性 15 4 丙戊酸的毒性 毒性 丙戊酸的代谢 16 4 丙戊酸的毒性 5 TAZ的毒性 口服胰岛素敏化剂用于II型糖尿病 退市 肝衰竭 甚至死亡 噻唑二酮环的氧化路径 Troglitazone 18 5 TAZ的毒性 苯并二氢吡喃环的氧化路径 Troglitazone 19 结论 几乎所有的代谢反应都能产生活性代谢产物 生物体内的这种变化可产生能直接或间接起作用的毒性化合物 毒性的出现可能是代谢物或活性中间体于生物靶相互作用的结果 烷化作用 Alkylation 致酶失活活性氧类化合物可导致细胞氧