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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 investigate the relationship between CYP3A5 gene polymorphism and CYP3A activity in patients with acute lymphoblastic leukemia (ALL) and plasma drug concentration of daunorubicin. Methods CYP3A5 * 3 genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing in 36 newly diagnosed ALL children. The expression of CYP3A5 mRNA was detected by real-time PCR. The activity of CYP3A was measured by the midazolam probe method, and the concentration of daunorubicin was determined by high performance liquid chromatography. Results The CYP3A5 mRNA expression levels were significantly different in children with different genotypes. CYP3A activity was significantly higher in children with CYP3A5 * 1 allele than those with * 3 alleles (P <0.05) There was a significant difference (P <0.05) between AUC0-24h and AUC0-∞, but the pharmacokinetic parameters such as t1 / 2 and Cmax had no statistical significance among the groups. AUC than the normal group significantly increased. Conclusion CYP3A5 mRNA expression, CYP3A activity, daunorubicin concentration and CYP3A5 * 3 gene polymorphism are closely related and produce different adverse drug reactions.