Guo Lei, Li Quanzhen, Xia Qingsu, Dial Stacey, Chan Po-Chuen, Fu Peter
Division of Systems Toxicology, National Center for Toxicological Research, FDA, 3900 NCTR Road, Jefferson, AR 72079, USA.
Food Chem Toxicol. 2009 Feb;47(2):433-42. doi: 10.1016/j.fct.2008.11.037. Epub 2008 Dec 7.
The association of kava product use with liver-related risks has prompted regulatory action in many countries. We studied the changes in gene expression of drug metabolizing enzymes in the livers of Fischer 344 male rats administered kava extract by gavage for 14 weeks. Analysis of 22,226 genes revealed that there were 14, 41, 110, 386, and 916 genes significantly changed in the 0.125, 0.25, 0.5, 1.0, and 2.0 g/kg treatment groups, respectively. There were 16 drug metabolizing genes altered in all three high-dose treatment groups, among which seven genes belong to cytochrome P450 isozymes. While gene expression of Cyp1a1, 1a2, 2c6, 3a1, and 3a3 increased; Cyp 2c23 and 2c40 decreased, all in a dose-dependent manner. Real-time PCR analyses of several genes verified these results. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, particularly the CYP isozymes, which could cause herb-drug interactions and may potentially lead to hepatotoxicity.
卡瓦产品的使用与肝脏相关风险之间的关联已促使许多国家采取监管行动。我们研究了通过灌胃给予卡瓦提取物14周的Fischer 344雄性大鼠肝脏中药物代谢酶的基因表达变化。对22226个基因的分析显示，在0.125、0.25、0.5、1.0和2.0 g/kg治疗组中，分别有14、41、110、386和916个基因发生了显著变化。在所有三个高剂量治疗组中，有16个药物代谢基因发生了改变，其中7个基因属于细胞色素P450同工酶。虽然Cyp1a1、1a2、2c6、3a1和3a3的基因表达增加；而Cyp 2c23和2c40的基因表达下降，均呈剂量依赖性。对几个基因的实时PCR分析验证了这些结果。我们的结果表明，卡瓦提取物可显著调节药物代谢酶，特别是CYP同工酶，这可能导致草药与药物相互作用，并可能潜在地导致肝毒性。
