环加氧酶及其药理学研究进展pdf

ChineseBulletinofLifeSciences17320056Vol.17,No.3Jun.,2005201203(cyclooxygenaseCOX)(prostaglandinsPGs)COXCOX-1COX-2COX-1COX-2Q55AAdvancesinthepharmacologyofcyclooxygenaseZHANGWei-Yu,ZHUXing-Zu*(ShanghaiInstituteofMateriaMedica,ShanghaiInstitutesforBiologicalSciences,ChineseAcademyofSciences,GraduateSchoolofCAS,Shanghai201203,China)Abstract:Cyclooxygenase(COX),arate-limitedenzymeinarachidonicacidmetabolicpathways,cancatalysethesynthesisofcyclicendoperoxidesfromarachidonicacidtoformprostaglandins(PGs).TwocyclooxygenaseisoformshavebeenidentifiedandreferredtoasconstitutiveCOX-1andinducibleCOX-2.Accordingtoapopularhypothesis,COX-1generates“good”prostaglandinsforphysiologicalhousekeepingfunctions,whileCOX-2formsthe“bad”prostaglandinsresponsibleforinflammatorysymptoms.However,recentdatashowthatthebiologicalfunctionsofprostanoidsformedbythetwoenzymesaremuchmorecomplexandinterrelatedthanpreviouslyappreciated.TheobjectiveofthearticleistoprovideanoverviewofrecentdevelopmentsinthefieldabouttheroleofCOXinvariousdiseases,andtodiscussthefeasibilityasapotentialtargetfortherapeutictreatment.Keywords:cyclooxygenase;prostaglandins;inflammation;neurodegenerativedisease;cardiovasculardisease;cancer;non-steroidalanti-inflammatorydrugs1004-0374(2005)03-0231-052005-01-132005-02-21No.04DZ14005(1973)(1946)*(COX)(prostaglandins,PGs)(thromboxane,TX)COX(1)G2(PGG2);(2)PGG2H2(PGH2)COXCOX-1COX-2COX-1COX-2COX-1232COX-2(non-steroidalanti-inflammatorydrugs,NSAIDs)COXNSAIDsCOX-1COX-2COX-1NSAIDsNSAIDsCOX-2COX-2celecoxibrofecoxibCOX-1COX-2[1]COX1COXCOX-2COX-2COX-2[2]celecoxibCOX-1[3]COX-1[48]COX-2E2(PGE2)COX-1COX-2COX-1COX-2COX-2COX-1COXCOX-2[9]COX-22h48h2h3.5PGE248h15-deoxy-D12−14-PGJ2COX-22h48hCOX-22COXCOX-1PGCOX-2(LPS)-1(IL-1)COX-2PGE2[1011]COX-2NSAIDs(Alzheimer’sdisease,AD)[12]COX-2[13]ADCOX-2β-(β-amyloid,Aβ)SH-SY5YCOX-2[14]1--4--1236-(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)COX-2JNK/c-Jun[15]COX-2COX-2(reactiveoxygenasespecies,ROS)[16]ROS(Parkinson’sdisease,PD)ROSCOX-2D2(PGD2)J2(PGJ2)COX-2[17]PGJ2233[18]COX-2COX-2COX-2MPTPPD[19]COXNSAIDsAD[20]NSAIDs(ibuprofen)(indomethacin)Aβ42[21]COXPGE2AβNSAIDsγ-(γ-secretase)[22]COX-23COX(atherosclerosis)COX-1A2(TXA2)COX-2I2(PGI2)[23]COX-1TXA2PGI2COX-2PGI2TXA2COX-2PGI2PGE2[24]Baker[25]/COX-2COX-2COX-2apoE[26][27](LDL)X(LXR)COX-2[28~29]COX-2COX-2TXA2COX-2[30]4COXCOX-2COX-1COX-2mRNA[31]C(PKC)RasCOX-2AP-1NF-IL6NF-κBNFATPEA3COX-2TATATATA(TATAbox)p53COX-2[32]p53COX-2COX-2COX-2COX-2mRNA3'AU(AU-enrichedelements)COX-2mRNACOX-2mRNACOX-2mRNA[31]COX-2COX-2COX-2[32]COX-2[33]COX-2(knockout)COX-2COX-1[34~35]COX-2COX-2COX-2COX-2234COX-2COX-2520COX-1COX-2COX-1COX-2[1]FunkCD.Prostaglandinsandleukotrienes:advancesineicosanoidbiology.Science,2001,294:1871~1875[2]NantelF,DenisD,GordonR,etal.Distributionandregula-tionofcyclooxygenase-2incarrageenan-inducedinflammation.BrJPharmacol,1999,128:853~859[3]AndersonGD,HauserSD,McGarityKL,etal.Selectiveinhibitionofcyclooxygenase(COX)-2reversesinflamma-tionandexpressionofCOX-2andinterleukin6inratadju-vantarthritis.JClinInvest,1996,97:2672~2679[4]SmithCJ,ZhangY,KoboldtCM,etal.Pharmacologicalanalysisofcyclooxygenase-1ininflammation.ProcNatlAcadSciUSA,1998,95:13313~13318[5]WallaceJL,ChapmanK,McKnightW.Limitedanti-inflam-matoryefficacyofcyclooxygenase-2inhibitionincarrag-eenan-airpouchinflammation.BrJPharmacol,1999,126:1200~1204[6]WallaceJL,BakA,McKnightW,etal.Cyclooxygenase1contributestoinflammatoryresponsesinratsandmice:implicationsforgastrointestinaltoxicity.Gastroenterology,1998,115:101~109[7]LangenbachR,MorhamSG,TianoHF,etal.Prostaglandinsynthase1genedisruptioninmicereducesarachidonicacid-inducedinflammationandindomethacin-inducedgastriculceration.Cell,1995,83:483~492[8]OchiT,GotoT.DifferentialeffectofFR122047,aselectivecyclooxygenase-1inhibitor,inratchronicmodelsofarthritis.BrJPharmacol,2002,135:782~788[9]GilroyDW,Colville-NashPR,WillisD,etal.Induciblecyclooxygenasemayhaveanti-inflammatoryproperties.NatMed,1999,5:698~701[10]BeicheF,ScheuererS,BruneK,etal.Upregulationofcyclooxygenase-2mRNAintheratspinalcordfollowingperipheralinflammation.FEBSLett,1996,390:165~169[11]CaoC,MatsumuraK,YamagataK,etal.EndothelialcellsofthebrainvasculatureexpressCOX-2mRNAinresponsetosystemicinterleukin-1:apossiblesiteofprostaglandinsyn-thesisresponsibleforfever.BrainRes,1996,733:263~272[12]McGeerPL,SchulzerM,McGeerEG.Arthritisandanti-inflammatoryagentsaspossibleprotectivefactorsforAlzheimer’sdisease:areviewof17epidemiologicstudies.Neurology,1996,47:425~432[13]ToccoG,FreireO,SchreiberSS,etal.Maturationalregulationandregionalinductionofcyclooxygenase-2inratbrain:im-plicationsforAlzheimer’sdisease.ExplNeurol,1997,144:339~349[14]PasinettiGM,AisenPS.Cyclooxygenase-2expressionisincreasedinfrontalcortexofAlzheimer’sdiseasebrain.Neuroscience,1998,87(2):319~324[15]TeismannP,TieuK,ChoiDK,etal.Cyclooxygenase-2isinstrumentalinParkinson’sdiseaseneurodegeneration.ProcNatlAcadSciUSA,2003,100:5473~5478[16]SairanenT,RistimakiA,Karjalainen-LindsbergML,etal.Cyclooxygenase-2isinducedgloballyininfarctedhumanbrain.AnnN