Grapefruit juice-drug interaction and the prediction

研究葡萄柚-药物相互作用以了解其机制和对药物治疗的影响。我们首先确定了葡萄柚汁中的致病化学物质为呋喃香豆素-香叶基衍生物，包括GF-I-1和GF-I-4。这些化学物质被发现是人类细胞色素P450，CYP 3A 4的强抑制剂。我们发现，少于50毫升的果汁摄入量改变了咪达唑仑的动力学特征，咪达唑仑是由CYP 3A 4代谢的。服用奥美拉唑的志愿者显示果汁对肠道CYP 3A 4的选择性影响。呋喃香豆素类通过竞争性和失活降低肠道CYP 3A 4，可能是通过中间复合物的形成。此外，我们发现葡萄柚摄入量抑制膳食致癌物PhIP诱导的DNA损伤。我们目前正在研究化学预防机制。为了评估果汁成分对CYP 3A 4诱导的影响，我们正在开发CYP 3A 4基因激活的体外测定系统。我们计划测试呋喃香豆素对CYP 3A 4的诱导作用。

Grapefruit-drug interaction was investigated to understand the mechanism and influence on drug therapy. We first identified the causative chemicals in grapefruit juice as furanocoumarin-geranylderivatives including GF-I-1 and GF-I-4. These chemicals were found to be strong inhibitors of a human cytochrome P450, CYP3A4. We showed that less than 50 ml intake of the juice altered the kinetic profile of midazolam, which was metabolized by CYP3A4. Selective influence of the juice on intestinal CYP3A4 was shown with volunteers taking omeprazole. Furanocoumarins were shown to decrease intestinal CYP3A4 by both competitive and inactivation, possibly through intermediate complex formation. In addition, we found that grapefruit intake suppress DNA lesion induced by dietary carcinogen PhIP. We are currently investigating the chemoprevention mechanism. To assess the influence of the juice component on CYP3A4 induction, we are developing the in vitro assay system of CYP3A4 gene activation. We have a plan to test the furanocoumarins for the inducibility of CYP3A4.