Ueng Yune-Fang, Ko Han-Chieh, Chen Chieh-Fu, Wang Jong-Jing, Chen Kuo-Tung
National Research Institute of Chinese Medicine, 155-1, Li-Nong Street, Sec. 2, Taipei 11211, Taiwan, ROC.
Life Sci. 2002 Aug 2;71(11):1267-77. doi: 10.1016/s0024-3205(02)01854-4.
Evodia rutaecarpa is a traditional Chinese medicine used for the treatment of gastrointestinal disorders and headache. To assess the possible drug interactions, effects of methanol and aqueous extracts of E. rutaecarpa on drug-metabolizing enzymes, cytochrome P450 (CYP), UDP-glucuronosyl transferase (UGT), and glutathione S-transferase (GST) were studied in C57BL/6J mice. Treatment of mice with methanol extract by gastrogavage caused a dose-dependent increase of liver microsomal 7-ethoxyresorufin O-deethylation (EROD) activity. In liver, methanol extract at 2 g/kg caused 47%, 7-, 8-, 4-fold, 81% and 26% increases of benzo(a)pyrene hydroxylation (AHH), EROD, 7-methoxyresorufin O-demethylation (MROD), 7-ethoxycoumarin O-deethylation (ECOD), benzphetamine N-demethylation, and N-nitrosodimethylamine N-demethylation activities, respectively. Aqueous extract at 2 g/kg caused 68%, 2-fold, and 83% increases of EROD, MROD, and ECOD activities, respectively. For conjugation activities, methanol extract elevated UGT and GST activities. Aqueous extract elevated UGT activity without affecting GST activity. Immunoblot analyses showed that methanol extract increased the levels of CYP1A1, CYP1A2, CYP2B-, and GSTYb-immunoreactive proteins. Aqueous extract increased CYP1A2 protein level. In kidney, both extracts had no effects on AHH, ECOD, UGT, and GST activities. Three major bioactive alkaloids rutaecarpine, evodiamine, and dehydroevodiamine were present in both extracts. These alkaloids at 25 mg/kg increased hepatic EROD activity. These results demonstrated that E. rutaecarpa methanol and aqueous extracts could affect drug-metabolizing enzyme activities. Rutaecarpine, evodiamine, and dehydroevodiamine contributed at least in part to the increase of hepatic EROD activity by extracts of E. rutaecarpa. Thus, caution should be paid to the possible drug interactions of E. rutaecarpa and CYP substrates.
吴茱萸是一种用于治疗胃肠道疾病和头痛的传统中药。为评估其可能的药物相互作用，在C57BL/6J小鼠中研究了吴茱萸甲醇提取物和水提取物对药物代谢酶细胞色素P450（CYP）、尿苷二磷酸葡萄糖醛酸基转移酶（UGT）和谷胱甘肽S -转移酶（GST）的影响。通过灌胃用甲醇提取物处理小鼠导致肝微粒体7 -乙氧基异吩恶唑酮O -脱乙基酶（EROD）活性呈剂量依赖性增加。在肝脏中，2 g/kg的甲醇提取物使苯并(a)芘羟化酶（AHH）、EROD、7 -甲氧基异吩恶唑酮O -脱甲基酶（MROD）、7 -乙氧基香豆素O -脱乙基酶（ECOD）、苄非他明N -脱甲基酶和N -亚硝基二甲胺N -脱甲基酶活性分别增加47%、7倍、8倍、4倍、81%和26%。2 g/kg的水提取物使EROD、MROD和ECOD活性分别增加68%、2倍和83%。对于结合活性，甲醇提取物提高了UGT和GST活性。水提取物提高了UGT活性而不影响GST活性。免疫印迹分析表明，甲醇提取物增加了CYP1A1、CYP1A2、CYP2B -和GSTYb -免疫反应性蛋白的水平。水提取物增加了CYP1A2蛋白水平。在肾脏中，两种提取物对AHH、ECOD、UGT和GST活性均无影响。两种提取物中均存在三种主要生物活性生物碱吴茱萸次碱、吴茱萸碱和脱氢吴茱萸碱。这些生物碱在25 mg/kg时增加了肝脏EROD活性。这些结果表明，吴茱萸甲醇提取物和水提取物可影响药物代谢酶活性。吴茱萸次碱、吴茱萸碱和脱氢吴茱萸碱至少部分促成了吴茱萸提取物引起的肝脏EROD活性增加。因此，应注意吴茱萸与CYP底物之间可能的药物相互作用。
