Department of Pharmacology, Basic Medical School, Beijing (Peking) University, 38 Xue-Yuan Road, Beijing, 100191, China.
J Clin Pharmacol. 2010 Jul;50(7):775-84. doi: 10.1177/0091270009354997. Epub 2010 Feb 16.
Interindividual variability of cytochrome P450 (CYP) 3A inhibition by grapefruit juice was investigated in relation to CYP3A5 and multidrug resistance gene (MDR) 1 genetic polymorphisms in Chinese Han, Uygur, and Kazakh healthy subjects. The measurement of urinary 6 beta-hydroxycortisol/cortisol ratio was used to evaluate CYP3A activity in vivo by high-performance liquid chromatography. CYP3A53 and MDR1 C1236T, G2677T/A, and C3435T polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism. After grapefruit juice intake, urinary ratios significantly decreased in 3 Chinese ethnic groups (P < .001). Kazakh had a larger decrease of urinary ratio compared to that of Han (P < .05), and the latter had similar decrease with Uygur. Furthermore, Chinese healthy subjects carrying CYP3A53/*3 and MDR1(1236-2677-3435) T-T-T/T-T-T genotypes were found to have the largest reduction of urinary ratio (mean, 61.4%; 95% confidence interval, 53.4%-69.5%), whereas *1/3 subjects carrying MDR1(1236-2677-3435) C-G-C/C-G-C genotypes had the lowest reduction (mean, 25.9%; 95% confidence interval, 3.1%-48.8%; P < .01). In conclusion, both CYP3A53 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice-drug interactions.
个体间细胞色素 P450（CYP）3A 被葡萄柚汁抑制的差异与中国汉族、维吾尔族和哈萨克族健康受试者的 CYP3A5 和多药耐药基因（MDR）1 遗传多态性有关。通过高效液相色谱法，采用尿 6β-羟基皮质醇/皮质醇比值来评估体内 CYP3A 活性。采用聚合酶链反应-限制性片段长度多态性分析 CYP3A53 和 MDR1 C1236T、G2677T/A 和 C3435T 多态性。葡萄柚汁摄入后，3 个民族的尿比值均显著降低（P<0.001）。与汉族相比，哈萨克族尿比值下降幅度更大（P<0.05），而汉族与维吾尔族相似。此外，携带 CYP3A53/3 和 MDR1（1236-2677-3435）T-T-T/T-T-T 基因型的中国健康受试者尿比值降低幅度最大（均值 61.4%，95%置信区间 53.4%-69.5%），而携带 MDR1（1236-2677-3435）C-G-C/C-G-C 基因型的1/3 受试者尿比值降低幅度最低（均值 25.9%，95%置信区间 3.1%-48.8%；P<0.01）。总之，CYP3A53 和 MDR1 变异体均影响了葡萄柚汁对中国健康受试者 CYP3A 的抑制程度。影响 CYP3A 抑制表型的遗传变异可能有助于解释葡萄柚汁与药物相互作用的个体差异。
