CYP2B6基因多态性与异维A酸人体代谢动力学差异关联性研究

Correlation analysis of CYP2B6 gene polymorphisms and pharmacokinetic parameters of isotretinoin in healthy human volunteers

目的 探讨细胞色素P450（CYP2B6）基因多态性与异维A酸人体代谢动力学的关系.方法 21例健康受试者单次口服40mg异维A酸胶丸（商品名泰尔丝）,提取外周血基因组DNA进行PCR及限制性核酸内切酶片段分析方法（RFLP）分析CYP2B6第四外显子exon4及第五外显子exon5基因分型.高效液相色谱-质谱法（LC/MS）分析受试者异维A酸血药浓度并计算相关药动学参数.结果 21例健康受试者CYP2B6 exon4及exon5存在明显的连锁不平衡性.等位基因CYP2B6^＊4野生型^＊1/^＊1为12例（57.14%）,杂合型^＊1/^＊4为6例（28.57%）,突变型^＊4/^＊4为3例（14.29%） 等位基因CYP2B6^＊6野生型^＊1/^＊1为13例（61.90%）,杂合型^＊1/^＊6为5例（23.81%）,变异型^＊6/^＊6为3例（14.29%）.等位基因CYP2B6^＊4野生型体内消除参数t1/2及MRT高于突变型（P值均＜0.05）,吸收参数Cmax、Tmax及AUC等两组差异无统计学意义.等位基因为CYP2B6^＊6的野生型与突变型各项药动学参数差异均未见有统计学意义（P＞0.05）.结论 代谢酶CYP2B6等位基因^＊4突变与异维A酸体内代谢相关.CYP2B6^＊4突变型可能为异维A酸快代谢型人群.

Objective To evaluate the association between isotretinoin pharmacokinetic parameters and CYP2B6 （cytochrome p-450） gene polymorphisms. Methods Blood samples were collected at different time points from 21 healthy male volunteers who received a single 40-rng oral dose of isotretinoin. High performance liquid chromatography-electrospray ionization mass spectrometry （LC-MS） was used for the quantification of isotretinoin in plasma samples which were standardized by dosage and body weight. PCR and restriction fragment length polymorphism （RFLP） analysis were performed to detect the G516T mutation in exon 4 as well as A785G mutation in exon 5 of CYP2B6 gene in these subjects. Results There was an obvious genetic linkage imbalance in exon 4 and 5 of CYP2B6 gene among these volunteers. In the case of CYP2B6^＊4 allele,3 （14.29%） people were CYP2B6^＊4/^＊4 homozygotes, 6 （28.57%） CYP2B6^＊1/＊4 heterozygotes, and 12 （57.14%） CYP2B6^＊1/^＊1 wild-type homogygotes, while as far as CYP2B6^＊6 allele was concerned, 3 （14.29%）people were CYP2B6^＊6/^＊6 homozygotes, 5 （23.81%） CYP2B6^＊1/^＊6 heterozygotes, and 13 （61.90%）CYP2B6^＊1/^＊1 wild-type homozygotes. The reaction half-time （t1/2） and mean residence time （MRT） of isotretinoin were longer in volunteers carrying wild-type CYP2B6^＊4 allele than those of CYP2B6^＊4/^＊4 homozygotes （both P 〈 0.05 ）, while no significant difference was observed in maximum concentration （Cmax）, peak time （Tmax） or area under the plasma concentration time （AUC） between the two groups of volunteers. There was no statistical difference in any of the above parameters between subjects carrying wild type CYP2B6^＊6 allele and those of CYP2B6 ^＊6/^＊6 homozygotes （all P 〉 0.05 ）. Conclusions The mutation of CYP2B6^＊4 allele ia relevant to the metabolism of isotretinoin, which seems to be more rapid in CYP2B6^＊4/^＊4 homozygotes.