柑橘类果汁对大鼠细胞色素P450 3A的抑制与果汁中呋喃香豆素组成的相关性

目的: 呋喃香豆素类(补骨脂素类) 是导致葡萄柚汁与药物相互作用的重要成分。本研究拟调查该类化合物在其它柑橘类果汁中的存在, 并比较这些果汁对细胞色素P450 (CYP) 3A 活性的抑制强度。方法: 用梯度高压液相色谱法测定柑橘类的鲜榨果汁中6 种呋喃香豆素化合物的组成与含量。以雄性Sprague-Dawley 大鼠肝微粒体的睾酮6β-羟化活性测试每种果汁对CYP3A 的抑制作用。结果: 与葡萄柚汁比较, Jaffa sweetie 果汁中呋喃香豆素的组成与含量基本相同, 对CYP3A 的抑制强度也相当;日本红柚、溪蜜柚和金柚的果汁中呋喃香豆素组成相似但含量较低, 对CYP3A 的抑制强度也较弱;常山胡柚、甜橙与宽皮橘果汁中呋喃香豆素种类少且含量极低, 且多数对CYP3A 无抑制作用。结论: 根据呋喃香豆素组成可以预测柑橘类果汁因为抑制CYP3A 引起的药物相互作用;王官溪蜜柚及近缘品种的果汁可能导致类似于葡萄柚汁的药物相互作用, 有必要在临床上加以验证。

Correlation of furanocoumarin composition and rat cytochrome P450 3A inhibition among citrus fruit juices

AIM: To investigate the existence of these compounds in other citrus fruit juices, and check their inhibitory intensities on activity of cytochrome P450 (CYP) 3A.METHODS: Freshly squeezed citrus fruit juices were determined separately for their composition and levels of six furanocoumarins with a gradient highpressure liquid chromatographic (HPLC) method. Inhibition of CYP3A by each juice sample was tested with the activity of testosterone 6β-hydroxylation in liver microsoms of male Sprague-Dawley rats.RESULTS: Comparing with grapefruit juices, the Jaffa sweetie showed almost the same composition and levels of furanocoumarins, and a comparable inhibitory intensity of CYP3A; the Japanese red pommelo, `Guanxi Miyou' and `Jinyou' pommelos showed similar compositions but lower levels of furanocoumarins, and weaker inhibiting intensities of CYP3A; While `Changshan Huyou' pummelos, sweet oranges and mandarins showed less varieties and much lower levels of furanocoumarins, and most of them showed no inhibition of CYP3A.CONCLUSION: Furanocoumarin composition can be an index to predict citrus fruit juice-drug interaction based on CYP3A inhibition; Clinical validations should be conducted on `Guanxi Miyou' pummelo and closely related accessions for their possible drug interactions similar to grapefruit juice.