金雀异黄酮对人CYP1A2、CYP2A6、NAT2及XO酶活性的影响

Effect of genistein on enzyme activities of CYP1A2,CYP2A6,NAT2 and XO in human

目的探讨金雀异黄酮在健康受试者体内对咖啡因主要代谢产物药代动力学的影响, 从而阐明金雀异黄酮对人CYP1A2、CTP2A6、NAT2及XO酶活性的影响。方法 18名健康受试者于试验第1天口服咖啡因100 mg后收集0~24 h的外周静脉血以及0~12h总尿液, 第2~15天服用金雀异黄酮1000 mg/d, 第16天早上服用探药咖啡因100mg, 第16天服用咖啡因后收集0~24h的外周静脉血以及0~12 h总尿液标本。血、尿标本中咖啡因及代谢产物的浓度采用高效液相色谱法(HPLC)定量检测, 计算血中咖啡因及主要代谢产物的药代动力学参数及各代谢物的尿液排泄量。结果与服用金雀异黄酮后相比, 受试者血浆中1, 7-二甲基黄嘌呤(17X)的药时曲线下面积(AUC(0-24 h)显著降低了11.77%(P=0.007)。尿液中17X和1-甲基黄嘌呤(1X)的排泄量分别显著降低了14.31%(P=0.027)和27.18%(P=0.002), 而1, 7-二甲基尿酸(17U)显著性增加了57.33%(P=0.028), 1-甲基尿酸(1U)显著降低了14.61%(P=0.028), 未发现尿液中咖啡因和5-乙酰氨基-6-甲酰氨基-3-甲基尿酸(AFMU)排泄量的变化。结论金雀异黄酮在体内影响了中国健康受试者咖啡因的主要代谢产物药代动力学, 通过对药物代谢活性酶的影响从而产生相应的药物相互作用。

Objective To investigate the action of genistein on major profiles of pharmacokinetics of caffeine in healthy subjects,and to clarify the effects of genistein on enzyme activities of CYP1A2,CTP2A6,NAT2 and XO in human.Methods A total of 18 healthy subjects were orally given 100 mg caffeine on day 1 of the test,and collected for 0~24 h peripheral venous blood and 0~12 h urine samples.On days 2 to 15,the subjects were given oral genistein 1000 mg/d.On day 16,they again received oral caffeine 100mg in the morning,and were then collected for 0~24 h peripheral venous blood and 0~12 h urine samples after taking caffeine.The levels of caffeine and its metabolites in blood and urine samples was quantitated by high performance liquid chromatography(HPLC).The pharmacokinetic profiles of caffeine and its major metabolites in the blood and urine excretion of the metabolites were calculated.Results After oral use of genistein,the area under the blood concentration-time curve[AUC(0-24 h)]of plasma 1,7-dimethylxanthine(17X)significantly decreased by 11.77%(P=0.007).Of the urine excretion,17X and 1-methylxanthine(1X)were significantly reduced by 14.31%(P=0.027)and 27.18%(P=0.002),respectively;1,7-dimethyluric acid(17U)increased by 57.33%(P=0.028);1-methyluric acid(1U)decreased by 14.61%(P=0.028);there were no changes in urine excretion of caffeine and 5-acetylamino-6-formylamino-3-methyluracil(AFMU).Conclusion Genistein alters the pharmacokinetics of major caffeine metabolites in healthy Chinese subjects through interference with active enzymes of drug metabolism.