基因多态性对丙戊酸钠及代谢物血药浓度的影响及其与不良反应的相关性研究

目的：研究细胞色素P450 2C9（CYP2C9）、尿苷葡萄糖醛酸转移酶（UGTs）、氨甲酰磷酸合酶1（CPS1）、线粒体聚合酶（POLG）、过氧化氢酶（CAT）、超氧化物歧化酶2（SOD2）基因多态性与丙戊酸钠(VPA)及其代谢物2-丙基-4-戊烯酸（４-ene-VPA）、2-丙基-2-戊烯酸（2-ene-VPA）的关系，探索代谢物浓度与肝功能损伤的相关性，为临床治疗提供依据。方法：收集99例癫痫患者共144份血液样本，记录患者肝功能指标，采用LC-MS/MS法检测VPA及其代谢物血药浓度，采用Snapshot技术检测UGT2B7（rs12233719、rs7668258）、UGT1A6（rs2070959、rs1105879、rs89910）、CAT rs1001179、SOD2 rs4880、CPS1 rs1047891、POLG rs3087374、CYP2C9 rs1057910基因型，比较不同基因型患者的VPA、４-ene-VPA及2-ene-VPA校正血药浓度差异，探索血药浓度与肝功能指标间的相关性。结果：UGT1A6 rs89910 CT型患者VPA、2-ene-VPA校正血药浓度高于CC型患者（P ＜ 0.05）；UGT2B7 rs7668258 TT型患者2-ene-VPA校正血药浓度低于CC/CT型（P ＜ 0.05）。同时发现VPA与4-ene-VPA血药浓度与肝功能指标相关，而CPS1 rs1047891 CC型患者丙氨酸氨基转移酶与碱性磷酸酶均低于AA/AC型患者（P ＜ 0.05）。结论：UGT1A6 rs89910、UGT2B7 rs7668258基因多态性与2-ene-VPA校正血药浓度相关。VPA及其代谢物４-ene-VPA可以引起肝功能损伤，CPS1 rs1047891 CC型患者比AA/AC型患者服用VPA后肝脏解毒能力更强。

Effects of Genetic Polymorphisms on Blood Concentrations of Valproic Acid and Its Metabolites and their Correlation with Adverse Reactions*

Objective: To investigate the relationship between the genetic polymorphisms of CYP2C9, UGTs, CPS1, POLG, CAT and SOD2 and the blood concentrations of valproic acid (VPA) and its metabolites 4-ene-VPA and 2-ene-VPA, and their relationship with liver function injury, so as to provide reference for clinical treatment. Methods: A total of 144 blood samples were collected from 99 epileptic patients. Liver function indexes of the patients were recorded. Blood concentrations of VPA and its metabolites were detected by an LC-MS/MS method. UGT2B7 (rs12233719, rs7668258), UGT1A6 (rs2070959, rs1105879, rs89910), CAT rs1001179, SOD2 rs4880, CPS1 rs1047891, POLG rs3087374 and CYP2C9 rs1057910 genotypes were detected by the Snapshot technology. The corrected blood drug concentrations of VPA, 4-ene-VPA and 2-ene-VPA of patients were compared among the above genotypes. The relationship between blood drug concentrations and liver function indicators were explored. Results: The corrected blood drug concentrations of 2-ene-VPA in UGT1A6 rs89910 CT and UGT2B7 rs7668258 CC/CT patients were higher than those in UGT1A6 rs89910 CC and UGT2B7 rs7668258 TT patients, respectively (P < 0.05). The blood concentrations of VPA and 4-ene-VPA were correlated with liver function indicators (P < 0.05). Compared with AA/AC type patients, CPS1 rs1047891 CC type patients had lower levels of alanine aminotransferase and alkaline phosphatase (P < 0.05). Conclusion: The UGT1A6 rs89910 and UGT2B7 rs7668258 genetic polymorphisms are associated with 2-ene-VPA drug concentrations. VPA and its metabolite 4-ene-VPA may be a factor of liver function damage, and patients with CPS1 rs1047891 CC type have stronger liver detoxification ability than those with AA/AC after administration of VPA.