Lee Sang Kyu, Kim Nam Hee, Lee Jaeick, Kim Dong Hyun, Lee Eung Seok, Choi Han-Gon, Chang Hyeun Wook, Jahng Yurngdong, Jeong Tae Cheon
College of Pharmacy, Yeungnam University, Kyungsan, Korea.
Planta Med. 2004 Aug;70(8):753-7. doi: 10.1055/s-2004-827207.
Rutaecarpine is an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa. Recently, rutaecarpine has been characterized to have an anti-inflammatory activity through cyclooxygenase-2 inhibition. In the present studies, the effects of rutaecarpine on liver cytochrome P450 s (P450s) and P450 s involved in the metabolism of rutaecarpine were studied in vivo and in vitro, respectively, because the data are crucial in the early development of rutaecarpine as a new drug candidate. Oral administration to male ICR mice of rutaecarpine for 3 consecutive days induced liver P450 1A-, 2B- and 2E1-selective monooxygenase activities. The induction of P450 1A and 2B by rutaecarpine was confirmed by Western immunoblotting. When rutaecarpine was incubated with rat liver microsomes in the presence of an NADPH-generating system, five metabolites were detected by UV and mass spectral analyses. The 3-methylcholanthrene- and phenobarbital-induced microsomes greatly increased the formation of metabolites. Our present results suggest that rutaecarpine might induce P450 1A and 2B in mice, and that P450 1A and 2B might predominantly metabolize rutaecarpine in rat liver microsomes.
吴茱萸碱是一种最初从吴茱萸未成熟果实中分离得到的生物碱。最近，研究发现吴茱萸碱可通过抑制环氧化酶-2发挥抗炎活性。在本研究中，分别在体内和体外研究了吴茱萸碱对肝细胞色素P450同工酶（P450s）以及参与吴茱萸碱代谢的P450同工酶的影响，因为这些数据对于吴茱萸碱作为一种新药候选物的早期开发至关重要。连续3天给雄性ICR小鼠口服吴茱萸碱可诱导肝脏P450 1A、2B和2E1选择性单加氧酶活性。通过蛋白质免疫印迹法证实了吴茱萸碱对P450 1A和2B的诱导作用。当在存在NADPH生成系统的情况下将吴茱萸碱与大鼠肝脏微粒体一起孵育时，通过紫外和质谱分析检测到了5种代谢产物。经3-甲基胆蒽和苯巴比妥诱导的微粒体大大增加了代谢产物的形成。我们目前的研究结果表明，吴茱萸碱可能在小鼠体内诱导P450 1A和2B，并且P450 1A和2B可能在大鼠肝脏微粒体中主要代谢吴茱萸碱。
