Furanocoumarins are the main compounds responsible for the food-drug interactions known as the grapefruit effect, which is caused by the inhibition of CYP3A4-mediated drug metabolism. We evaluated the effects of two new, low-furanocoumarin grapefruit cultivars on CYP3A4 activity and the roles of different furanocoumarins, individually and together with other juice compounds, in the inhibition of CYP3A4 by grapefruit. Whereas a standard grapefruit cultivar inhibited CYP3A4 activity in a dose-dependent manner, neither of the two examined low-furanocoumarin cultivars had an inhibitory effect. Despite the fact that bergamottin and 6',7'-dihydroxybergamottin are weak inhibitors of CYP3A4, their relatively high levels in grapefruit make them the leading cause of the grapefruit effect. We found that furanocoumarins together with other juice compounds inhibit CYP3A4 in an additive manner. In silico docking simulation was employed, and differentiated between high- and low-potency inhibitors, suggesting that modeling may be useful for identifying potentially harmful food-drug interactions.

中文翻译：

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新的葡萄柚品种表现出低的细胞色素P4503A4-抑制活性。

呋喃香豆素是负责食品与药物相互作用的主要化合物，被称为葡萄柚效应，这是由于抑制CYP3A4介导的药物代谢所致。我们评估了两种新的低呋喃香豆素葡萄柚品种对CYP3A4活性的影响以及不同的呋喃香豆素单独和与其他果汁化合物一起在葡萄柚对CYP3A4抑制中的作用。尽管标准葡萄柚品种以剂量依赖的方式抑制CYP3A4活性，但两个检测到的低呋喃香豆素品种均没有抑制作用。尽管bergamottin和6'，7'-dihydroxybergamottin是CYP3A4的弱抑制剂，但它们在葡萄柚中的相对较高水平使其成为葡萄柚作用的主要原因。我们发现呋喃香豆素与其他果汁化合物一起以加性方式抑制CYP3A4。在计算机模拟中使用了对接模拟，并区分了高效抑制剂和低效抑制剂，这表明建模可用于识别潜在有害的食品与药物的相互作用。