CYP2C19、CYP2D6基因多态性与精神分裂症患者氯氮平代谢的关联研究

Correlation between CYP2C19 and CYP2D6 gene polymorphism and Clozapine metabolism in patients with schizophrenia

目的探讨精神分裂症患者CYP2C19、CYP2D6基因多态性对氯氮平(CZ)代谢的影响。方法采用实时荧光定量PCR检测224例精神分裂症患者的CYP2C19与CYP2D6基因型,根据CYP2C19的代谢类型,将患者分为快代谢型、中间代谢型和慢代谢型,根据CYP2D6的代谢类型,将患者分为快代谢、中间代谢型和中低代谢型。高效液相色谱技术检测各组患者氯氮平及其代谢产物去甲氯氮平(NCZ)的血药浓度。分别计算各组基因型分布和等位基因频率、CZ、NCZ、CZ+NCZ总血药浓度以及NCZ/CZ比值。结果224例精神分裂症患者CYP2C19等位基因*1、*2和*3的基因频率分别为62.3%、33.9%和3.8%。CYP2D6等位基因*1、*2、*4、*10和*41的基因频率分别为22.3%、11.8%、0.7%、61.2%和4.0%。CYP2C19快代谢型NCZ/CZ比值为0.41±0.31,CYP2C19中间代谢型NCZ/CZ比值为0.39±0.19,CYP2C19慢代谢型的NCZ/CZ为0.30±0.12,CYP2C19快代谢型、CYP2C19中间代谢型NCZ/CZ比值高于CYP2C19慢代谢型,差异有统计学意义(F=9.11,P<0.05)。结论CYP2C19可影响CZ的代谢,且CYP2C19慢代谢型显著降低CZ代谢率。CYP2D6对CZ代谢影响不显著。

Objective To investigate the effects of CYP2C19 and CYP2D6 polymorphism on Clozapine(CZ)metabolism in schizophrenic patients.Methods The genotypes of CYP2C19 and CYP2D6 were detected by real-time fluorescence PCR technology in 224 schizophrenic patients.According to the metabolic type,the patients with CYP2C19 were classified into extensive metabolizers,intermediate metabolizers and poor metabolizers,and the patients with CYP2D6 were divided into extensive metabolizers,intermediate metabolizers and moderate to low metabolizers.The concentrations of clozapine and norclozapine(NCZ)in the serum of all patients were detected by high performance liquid chromatography.The genotype distribution,allele frequency,concentrations of CZ,NCZ,CZ+NCZ and the ratios of NCZ/CZ concentration in each group were calculated respectively.Results The frequency of CYP2C19 alleles*1,*2 and*3 was 62.3%,33.9%and 3.8%,respectively.The frequency of CYP2D6 alleles*1,*2,*4,*10 and*41 was 22.3%,11.8%,0.7%,61.2%and 4.0%,respectively.The NCZ/CZ ratio in the group of CYP2C19 extensive metabolic type was(0.41±0.31),in the group of CYP2C19 intermediate metabolic type was(0.39±0.19),and in the group of CYP2C19 poor metabolic type was(0.30±0.12).NCZ/CZ ratios of CYP2C19 extensive metabolizers and intermediate metabolizers were higher than that of CYP2C19 poor metabolizers with significant difference(F=9.11,P<0.05).Conclusion CYP2C19 gene in the schizophrenic patients could affect CZ metabolism,and its metabolism rate significantly reduced in the poor metabolizers,but no significant effect of CYP2D6 gene on CZ metabolism was found.