急性淋巴细胞白血病患儿CYP3A5基因多态性对柔红霉素代谢和不良反应的研究  

Effects of CYP3A5 genetic polymorphism on doxorubicin pharmacokinetics and toxicity in acute lymphoblastic leukemia patients

作　　者：黄珍[1] 童洪飞[2] 陈敏[1] 曾炜炜[1] 李原[1] 

机构地区：[1]温州医科大学附属第二医院、育英儿童医院血液科,浙江温州325003 [2]温州医科大学附属第二医院肝胆外科,浙江温州325003

出　　处：《中国临床药理学杂志》2015年第6期443-446,共4页The Chinese Journal of Clinical Pharmacology

摘　　要：目的探讨急性淋巴细胞白血病(ALL)儿童CYP3A5基因多态性与CYP3A酶活性、柔红霉素的血浆药物浓度的关系。方法 36例初治ALL患儿用聚合酶链-限制性片段长度多态性方法及聚合酶链式反应(PCR)产物测序法检测CYP3A5*3基因型,实时定量PCR法测定CYP3A5 mRNA表达水平。咪达唑仑探针法测CYP3A酶活性,并用高效液相色谱法测定柔红霉素浓度。结果不同基因型患儿的CYP3A5 mRNA表达水平差异较大;含CYP3A5*1等位基因的患儿CYP3A酶活性高于含*3等位基因者(P<0.05);不同基因型患儿柔红霉素AUC0-24h和AUC0-∞有显著性差异(P<0.05),而t1/2和Cmax等药代动力学参数在各组间差异无统计学意义;出现心脏毒性的ALL患儿柔红霉素的AUC较正常组明显增大。结论 CYP3A5 mRNA表达水平、CYP3A酶活性、柔红霉素血药浓度与CYP3A5*3基因多态性密切相关,并产生不同的药物不良反应。Objective To explore the association between genetic polymorphism of CYP3A5 and CYP3 A enzyme activity as well as the pharmacokinetics of doxorubicin. Methods The distribution of genotype of CYP3A5 gene polymorphism in 36 patients with acute lymphoblastic leukemia（ ALL） was analyzed with polymerase chain reaction- restriction fragment length polymorphism method and quantitative real- time RT- PCR was used to test the levels of CYP3A5 mRNA. The CYP3 A enzyme activity was detected by midazolam and high performance liquid chromatography was employed to determine the plasma concentration of daunorubicin. Results There were significant differences in CYP3A5 mRNA levels among individual genotype. Patients with CYP3A＊ 1 gene had a higher activity of CYP3 A enzyme than those with CYP3A5＊ 3 gene（ P〈 0. 05）. There were significant differences in AUC0- 24 hand AUC0- ∞among CYP3A5 genotype in patients with ALL（ P〈 0. 05）. No significant difference of t1 /2and Cmaxwas observed. The data of AUC significantly enlarged in patients with cardiac toxicity. Conclusion The expression of CYP3A5 mRNA,activity of CYP3 A enzyme and the plasma concentration of daunorubicin are closely related to CYP3A5 ＊ 3 genetic polymorphism. As a result it has an influence on the ALL patients with different adverse reactions.

关 键 词：个体化治疗 CYP3A5 基因多态性 CYP3A酶活性 柔红霉素 

分 类 号：R733.71[医药卫生—肿瘤]