Department of Twin Research and Genetic Epidemiology, St Thomas' Hospital, London, UK.
Pharmacogenet Genomics. 2011 Oct;21(10):642-51. doi: 10.1097/FPC.0b013e3283498ecf.
The cytochrome P450 3A4 (CYP3A4) enzyme is implicated in the metabolism of more than 50% of all prescribed medications and its activity - including induced or inhibited activity - is deemed to be a crucial determinant of interindividual variability in drug disposition, poor therapeutic efficacy, and adverse response to medication.
We used the classical twin model in conjunction with an induction experiment to uncover the relative contribution of genetic and environmental factors to interindividual variation in induced CYP3A4 activity. A total of 367 healthy twins participated in the study. Each volunteer was administered a potent inducer of CYP3A4 (St John's Wort) for 14 days and the activity of CYP3A4 was quantified through the metabolism of the exogenously administered probe drug quinine sulfate.
Baseline and induced CYP3A4 activity were highly variable with a seven-fold and 11-fold difference among our population, respectively. Alcohol consumption, BMI, and smoking were significantly associated with induced CYP3A4 activity, collectively explaining 20% of the variation (P<1×10(-4)). The narrow-sense heritability of induced CYP3A4 activity was estimated at 66%, whereas the remainder of the variation was attributed to unique environmental factors.
To our knowledge, this is the first genetic epidemiological study of induced CYP3A4 activity. Our results motivate further research to identify common and rarer genetic variants that underpin the heritable component of variation in induced CYP3A4 activity.
细胞色素 P450 3A4（CYP3A4）酶参与代谢超过 50%的所有处方药，其活性（包括诱导或抑制活性）被认为是药物处置、治疗效果不佳和药物不良反应个体间差异的关键决定因素。
我们使用经典的双胞胎模型结合诱导实验来揭示遗传和环境因素对 CYP3A4 诱导活性个体间变异的相对贡献。共有 367 名健康双胞胎参与了这项研究。每个志愿者服用一种强效 CYP3A4 诱导剂（贯叶连翘）14 天，并通过外源性给予的探针药物硫酸奎宁的代谢来定量 CYP3A4 的活性。
基线和诱导的 CYP3A4 活性变化很大，在我们的人群中分别有 7 倍和 11 倍的差异。饮酒、BMI 和吸烟与诱导的 CYP3A4 活性显著相关，共同解释了 20%的变异（P<1×10(-4)）。诱导的 CYP3A4 活性的狭义遗传力估计为 66%，而其余的变异归因于独特的环境因素。
据我们所知，这是诱导 CYP3A4 活性的第一项遗传流行病学研究。我们的结果促使进一步研究以确定常见和罕见的遗传变异，这些变异是诱导 CYP3A4 活性遗传变异的基础。
