细胞色素P450酶2A6、2B6、2C9及2C19基因多态性对丙戊酸钠血药浓度的影响

摘要

目的 探讨细胞色素P450酶2A6(CYP2A6)、2B6(CYP2B6)、2C9(CYP2C9)和2C19(CYP2C 19)基因多态性对丙戊酸钠血药浓度的影响.方法 选择单药服用丙戊酸钠的癫痫患儿131例,应用多重PCR方法对CYP2A6*4基因多态性进行检测,应用PCR-连接酶检测反应技术对CYP2 B6*6、CYP2C9*2、CYP2C9*3、CYP2C19*2和CYP2C19*3基因多态性进行检测,应用均相酶放大免疫分析法测定丙戊酸钠血药浓度,采用单因素方差分析方法或t检验进行统计学分析.结果 患儿根据CYP2C9、CYP2C19基因型分为4组:G1组(CYP2C9和CYP2C19均为强代谢者)、G2组(CYP2C19中间代谢者)、G3组(CYP2C19弱代谢者)和G4(CYP2C9弱代谢者)；G3(3.70±0.95)、G4组(4.35±1.48)标准化血药浓度显著高于G1组(2.57±1.30,t=3.056、4.490,均P＜0.01)和G2组(2.76±1.19,t=2.827、4.462,均P＜0.01)；G3(19.46±5.20)、G4组(19.30 ±7.67)丙戊酸钠剂量(mg/d)显著低于G1组(24.10±6.97,t=2.359、2.297,均P＜0.05).未发现突变型CYP2A6*4和CYP2B6*6对丙戊酸钠剂量和丙戊酸钠标准化血药浓度的影响.结论 CYP2C9和CYP2C19基因多态性会影响丙戊酸钠血药浓度,弱代谢(G3和G4组)的患儿服用丙戊酸钠应适当减少剂量.%Objective To investigate the influences of the functional polymorphisms of cytochrome P450 isozymes 2A6 (CYP2A6),2B6 (CYP2B6),2C9 (CYP2C9),and 2C19 (CYP2C19) on plasma concentration of sodium valproate.Methods A total of 131 Chinese children with epilepsy receiving sodium valproate after a period of more than 5 half-time were recruited.The genotypes of CYP2A6 were detected by multiplex polymerase chain reaction (PCR),and the genotypes of CYP2B6,CYP2C9,and CYP2C19 were detected by PCR-ligase detection reaction.Enzyme-multiplied immunoassay technique was used to measure the plasma concentration of sodium valproate.The association between the polymorphisms and the plasma concentration of sodium valproate were analyzed by one-way ANOVA or Student' s t-test.Results Patients were divided into 4 groups according to the genotyping results of CYP2C9 and CYP2C19 (G1:extensive metabolizers in both CYP2C9 and CYP2C19; G2:CYP2C19 intermediate metabolizers; G3:CYP2C19 poor metabolizers; G4:CYP2C9 poor metabolizers),the mean normalized steady-state sodium valproate concentrations were significantly higher in G3 (3.70 ± 0.95) and G4 (4.35 ± 1.48) patients when compared to those in G 1 (2.57 ± 1.30,t =3.056,4.490,both P ＜ 0.01) and G2 (2.76 ± 1.19,t =2.827,4.462,both P ＜ 0.01) patients.The daily doses (mg/d) of sodium valproate received by G3 (19.46 ± 5.20) and G4 (19.30 ±7.67) patients were significantly lower than that of G1 patients(24.10 ±6.97,t =2.359,2.297,both P ＜ 0.05).There were no differences in daily doses or normalized steady-state concentrations of sodium valproate among the CYP2A6* 4 or CYP2B6* 6 genotypic groups.Conclusions The CYP2C9 and CYP2C19 polymorphisms have dramatic effects on the plasma concentration of sodium valproate.The daily doses of sodium valproate in G3 and G4 patients should be lower than usual.