尿苷二磷酸葡萄糖醛酸转移酶1A6基因多态性对丙戊酸钠代谢的影响

Effect of UGT1A6 genetic polymorphisms on the metabolism of sodium valproate

目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A6(UGTlA6)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且无肝肾功能异常的癫痫患者67例,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法分析患者的 UGT1A6基因552位点的多态性;同时应用荧光偏振免疫法(FPIA)测定患者丙戊酸钠的血药浓度。结果 67例患者中 UGT1A6的552位点基因型为 A/A,A/C 及 C/C 的例数分别40(59.7%)、24(35.8%)及3(4.5%)。A/A 组标准血药浓度均值(4.32±0.21)μg·kg·ml^(-1)·mg^(-1)和 A/C 组(3.43±0.30)μg·kg·ml^(-1)·mg^(-1)比较差异有统计学意义;含有 C 等位基因的 A/C 及 C/C 作为一组[标准血药浓度均值(3.40±0.28)μg·kg·ml^(-1)·mg^(-1)]与 A/A 组比较,其标准血药浓度均值差异具有统计学意义。结论 UGT1A6是丙戊酸钠的代谢酶,UGT1A6基因多态性可影响丙戊酸钠的代谢,UGT1A6基因552位点含有 C 等位基因的患者应用丙戊酸钠应较常规增加用药剂量。

Objective To investigate the effect of UGT1A6 genetic polymorphisms on the serum concentration of sodium valproate so as to help better individualize the medication for patients with epilepsy. Methods Peripheral blood samples were collected for 67 patients receiving sodium valproate after more than 5 half-time periods, aged 17.5 （5-52）. The genotypes of UGT1A6 were detected by polymerase chain reaction-restriction fragment length polymorphism （PCR-RFLP） assay to examine the alleles 552A→C . Fluorescence polarization immunoassay （FPIA） was used to measure the serum concentration of sodium valproate and the results were standardized by dosage and body weight. Result Out of the 67 cases, 40 （59.7%） were with the wild genotype of UGT1A6 gene, 24 （35.8%） were with the A/C genotype, and 3 （4.5%） were with the C/C genotypes. The frequencies of 552A→C were 22.4%. The mean value of the serum concentration of sodium valproate with A/A genotype was 4.32 ± 0.2, significantly higher than that of the patients with A/C genotype （ 3.43 ± 0. 30, P 〈 0. 05 ）. When the genotypes A/C and C/C were considered as a group, the mean value of the serum concentration of sodium valproate was 3.40 ± 0.28, significantly lower than that of the patients with A/A genotype （P 〈 0.05）. Conclusions Sodium valproate is metabolized via uridine diphospho-glucuronosyltransferase. The genetic polymorphisms of UGT1A6 gene affect the metabolism of sodium valproate. The dosage of sodium valproate for the patients with 552C allele in UGT1A6 should be more than the usual dosage.