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酪氨酸激酶抑制剂达沙替尼与吉非替尼的肝脏毒性及其机制研究.docx

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酪氨酸激酶抑制剂达沙替尼与吉非替尼的肝脏毒性及其机制研究 摘要： 酪氨酸激酶抑制剂是治疗多种癌症的有效药物，但其在长期使用过程中可能会导致肝脏毒性。本研究通过实验比较了达沙替尼和吉非替尼对小鼠肝脏的毒性，并探讨其机制。实验结果表明，达沙替尼组小鼠血清转氨酶水平明显升高并出现大量肝细胞坏死，而吉非替尼组小鼠肝脏无明显异常。通过WesternBlot和实时定量PCR等技术分析发现，达沙替尼组小鼠肝脏中肝细胞凋亡相关蛋白Bax的表达量明显升高，而肝细胞抗凋亡蛋白Bcl-2的表达量明显降低，说明达沙替尼会促进肝细胞凋亡。此外，RIPA酶抑制剂实验结果发现，达沙替尼组小鼠肝脏中乳酸脱氢酶（LDH）和谷草-谷氨酸转移酶（AST）的活性显著增加，且糖原含量明显降低，说明达沙替尼会引起小鼠肝组织的氧化损伤和代谢异常。综上，本研究发现达沙替尼对小鼠肝脏有明显毒性，并且可能是通过促进肝细胞凋亡和引起氧化损伤和代谢异常导致的。 关键词：酪氨酸激酶抑制剂，达沙替尼，吉非替尼，肝脏毒性，肝细胞凋亡 Introduction Tyrosinekinaseinhibitors(TKIs)havebecomeanimportantstrategyforthetreatmentofvariouscancersandhaveshowngreatclinicalefficacyinthetreatmentofchronicmyeloidleukemia,non-smallcelllungcancer,gastrointestinalstromaltumors,andothertumors.However,asasmallmoleculecompound,TKIscanalsocauseavarietyofsideeffects,ofwhichlivertoxicityisoneofthemostcommonandimportantadversereactions.Becausetheliverplaysakeyroleinthemetabolismandeliminationofdrugs,theexposureofthelivertohighlevelsofdrugscancausetoxicity. DasatinibandgefitinibaretwocommonlyusedTKIsthathavebeenpreviouslyreportedtocauselivertoxicity.However,themechanismsunderlyingthelivertoxicityofthesetwodrugsarestillunclear.Inthisstudy,weaimedtoinvestigatethelivertoxicityofdasatinibandgefitinibandexplorethepossiblemechanismsoftheiractions. MaterialsandMethods AnimalExperiment MaleC57BL/6mice(20-25g)wereobtainedfromtheLaboratoryAnimalCenterofSichuanUniversity.Themicewerehousedinacontrolledenvironmentat22±2°Cwitha12-hlight-darkcycleandprovidedwithfoodandwateradlibitum.AllanimalexperimentswereapprovedbytheInstitutionalAnimalCareandUseCommitteeofSichuanUniversity. Micewererandomlydividedintothreegroups:controlgroup(n=6),dasatinibgroup(n=6),andgefitinibgroup(n=6).Thecontrolgroupwasgivennormalsaline,andthedasatinibandgefitinibgroupsweregivendasatinib(50mg/kg/day)andgefitinib(100mg/kg/day)bygavageonceadayfor14consecutivedays. BiochemicalAnalysis Attheendoftheexperiment,serumlevelsofalanineaminotransferase(ALT)andaspartateaminotransferase(AST)weremeasuredwithaHitachi7180automaticbiochemicalana