CYP2D6基因多态性及对药物代谢的影响-韩璐

CN341206/R,ISSN10092501(1):105-11020101101收稿20101225修回国家自然科学基金项目(30600774及81070902);教育部新世纪优秀人才支持计划(NCET080567);2010年中南大学硕士生学位论文创新资助项目资助韩璐,女,硕士研究生,研究方向:临床药理学遗传药理学Tel:073184805380Email:[e-mail]刘洁,通信作者,女,博士,副教授,硕士研究生导师,研究方向:临床药理学遗传药理学Tel:073184805380Email:[e-mail]2D6基因多态性及对药物代谢的影响韩璐,刘洁中南大学临床药理研究所,长沙410078,湖南CYP2D6代谢酶是细胞色素P450家族中的成员之一,是参与相代谢和众多内源性物质和不同药物消除的酶虽然它在肝脏中的含量大约只占肝脏总量的2%,但在临床上却参与了25%以上的常用药物的代谢活动在所有参与药物代谢的细胞色素P450基因家族中,CYP2D6是唯一不能被诱导的酶,这种酶具有广泛的多态性,这种多态性对酶的药物代谢功能具有重要影响,CYP2D6的这种多态性和药物代谢功能所表现的对个体活性的差异,在遗传药理学上具有重要意义本文从CYP2D6基因多态性和它对药物代谢的影响这两方面进行了阐述CYP2D6;基因多态性;药物代谢:R969:A:10092501(2011)010105061P450(CYP450),,P450CYP2D6P450,22131,25%[1],()()()P450,CYP2D6,CYP2D6,90,,,,(1)[2]2CYP2D62.1CYP2D65%~10%(PMs),1%,,CYP2D6,,0.6,1.0,1000,,105[3]1CYP2D6图中只列出有表型意义的等位基因,其中九个外显子用标有数字的方框表示DNA的改变表示在其上方,氨基酸的改变和终止密码子表示在其下方可读框用阴影框表示沉默子启动子内含子以及一些不确定的等位基因没有在图中表示出来1CYP2D6[4]CYP2D6(UM,EM,IMOrPMallele)/CYP2D61EM1CYP2D61N(N2)UM1NCYP2D62EM1CYP2D62N(N=2-5or13)UM1NCYP2D63PM0CYP2D64PM0CYP2D642PM0106ChinJClinPharmacolTher2011Jan;16(1)CYP2D6(UM,EM,IMOrPMallele)/CYP2D65PM0CYP2D66PM0CYP2D67PM0CYP2D68PM0CYP2D69PM0.7CYP2D610IM0.2CYP2D610NIM0.2NCYP2D614PM0CYP2D617IM0.5CYP2D617NEM(N=2)0.5N(N=2)CYP2D618PM0CYP2D621PM0CYP2D629IM0.7CYP2D635EM1CYP2D6352UM2CYP2D636IM0.05CYP2D636-10IM0.25CYP2D6362IM0.1CYP2D641IM0.5CYP2D6412EM1CYP2D644PM02.2CYP2D6,CYP2D6,,,,53,,95%,,CYP2D6*4,CYP2D6*3CYP2D6*5,,CYP2D6*9,,CYP2D6*2CYP2D6*2CYP2D6*1,,CYP2D6,40%[5-7](1)CYP2D6,CYP2D6*3CYP2D6*4,CYP2D6*5,34/,CYP2D6*10,CYP2D6[8]CYP2D6*1050%,5%,,CYP2D6*21072011Jan;16(1)3CYP2D6CYP2D6(2%),,CYP2D690,25%,(2)CYP2D6[9],CYP2D6,CYP2D630%~50%,,,M[10]2CYP2D6N3.1CYP2D6CYP2D6,CYP2D6,,CYP2D6,/,,[11]3.2CYP2D6CYP2D6,,,,CYP2D6N4,4N,,[12-13]3.3CYP2D6CYP2D6,[14],,,,CYP2D67[14]CYP2D6,,[16-17]CYP2D6,CYP2D6108ChinJClinPharmacolTher2011Jan;16(1),,(CYP2D6),,[18]CYP2D6,CYP2D6,[19],,,CYP2D6,CYP2D6[20-21]CYP2D6,N[22],,7[23-24],9CYP2D64CYP2D6P450,,,,,CYP2D6,,,,,[1]IngelmanSundbergM,SimSC,GomezA,etal.InfluenceofcytochromeP450polymorphismsondrugtherapies:pharmacogenetic,pharmacoepigeneticandclinicalaspects[J].PharmacolTher,2007,116(3):496-526.[2]EvansDA,HarmerD,DownhamDY,etal.Thegeneticcontrolofsparteineanddebrisoquinemetabolisminmanwithnewmethodsofanalysingbimodaldistributions[J].JMedGenet,1983,20(5):321-329.[3]MahgoubA,IdleJR,SmithRL,etal.ApopulationandfamilialstudyofdefectivealicyclichydroxylationofdebrisoquineamongEgyptians[J].Xenobiotica,1979,9(1):51-56.[4]YokotaH,TakamuraS,FuruyaH,etal.EvidenceforanewvariantCYP2D6alleleCYP2D6JinaJapanesepopulationassociatedwithlowerinvivoratesofsparteinemetabolism[J].Pharmacogenetics,1993,3(5):256-263.[5]DahlML,JohanssonI,BertilssonL,etal.UltrarapidhydroxylationofdebrisoquineinaSwedishpopulation.Analysisofthemoleculargeneticbasis[J].JPharmacolExpTherapeut,1995,274(1):516-520.[6],.P4502D6[J].,2006,11(4):369-374.[7],,.P450[J].,2007,16(7):510-515.[8]RendicS.SummaryofinformationonhumanCYPenzymes:humanP450metabolismdata[J].DrugMetabRev,2002,34(1/2):83-448.[9]BoinaN,TramiakI,MedvedV,etal.CYP2D6genotypeandpsychotropicdruginducedadverseeffects[J].PeriodBoil,2001,103(1):309-314.[10]PreskornSH,GreenblattDJ,FlockhartD,etal.Comparisonofduloxetine,escitalopram,andsertralineeffectsoncytochromeP4502D6functioninhealthyvolunteers[J].JClinPsychopharmacol,2007,27(1):28-34.[11]GascheY,DaaliY,FathiM,etal.CodeineintoxicationassociatedwithultrarapidCYP2D6metabolism[J].NewEnglJMed,2004,351(27):2827-2831.[12]DalyAK,BrockmollerJ,BrolyF,etal.NomenclatureforhumanCYP2D6alleles[J].Pharmacogenetics,1996,6(3):193-201.[13]ZangerUM,RaimundoS,EichelbaumM,etal.CytochromeP4502D6:overviewandupdateonpharmacology,genetics,biochemistry[J].NaunynSchmiedeberg'sArchPharmacol,2004,369(1):23-37.1092011Jan;16(1)[14]IngelmanSundbergM,SimSC,GomezA,etal.InfluenceofcytochromeP450polymorphismsondrugtherapies:Pharmacogenetic,pharmacoepigeneticandclinicalaspects[J].PharmacolTher,2007,116(3):496-526.[15]EichelbaumM,IngelmanSundbergM,EvansWE,etal.Pharmacogenomicsandindividualizeddrugtherapy[J].AnnuRevMed,2006,57:119-137.[16]BertilssonL,DahlML,DalenP,etal.MoleculargeneticsofCYP2D6:clinicalrelevancewithfocusonpsychotropicdrugs[J].BrJClinPharmacol,2002,53(2):111-122.[17]GurleyBJ,SwainA,HubbardMA,etal.ClinicalassessmentofCYP2D6mediatedherbdruginteractionsinhumans:effectsofmilkthistle,blackcohosh,goldenseal,kavakava,St.John'swort,andEchinacea[J].MolNutrFoodRes,2008,52(7):755-763.[18]BozinaN,BradamanteV,LovriM.GeneticpolymorphismofmetabolicenzymesP450(CYP)asasusceptibilityfactorfordrugresponse,toxicity,andcancerrisk[J].ArhHigRadaToksikol,2009,60(2):217-242[19]WuttkeH,RauT,HeideR,etal.IncreasedfrequencyofcytochromeP4502D6poormetabolizersamongpatientswithmetoprololassociatedadverseeffects[J].ClinPharmacolTher,2002,72(4):429-437.[20]LamYW,GaedigkA,EreshefskyL,etal.CYP2D6inhibitionbyselectiveserotoninreuptakeinhibitors:analysisofachievablesteadystateplasmaconcentrationsandtheeffectofultrarapidmetabolismatCYP2D6[J].Pharmacotherapy,2002,22(8):1001-1006.[21]KirchheinerJ,NickchenK,BauerM,etal