Fujisaki H, Mise M, Ishii Y, Yamada H, Oguri K
Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
J Pharmacol Exp Ther. 1994 Feb;268(2):1024-31.
The inducing activities of two alkaloids, strychnine and brucine, on the hepatic drug metabolizing enzymes were studied in rats. Administration of strychnine in the drinking water to rats significantly increased the hepatic microsomal activities of benzphetamine N-demethylation, strychnine 2-hydroxylation and testosterone hydroxylations at positions 16 alpha and 16 beta. These results together with that of immunostaining of microsomal proteins revealed that strychnine is a potent inducer of CYP2B1 and 2B2. The comparable induction of CYP2B1/2 was observed by brucine treatment with less toxic effect. Although this inducer increased CYP2B cytochrome P450s (P450s) to the maximum levels after 4 consecutive days of administration, the maximal increase by strychnine was attained after 3 days of administration. Immunoblotting experiment suggested that significant proteolysis of CYP2B1 occurs during treatment by strychnine and brucine. These alkaloids exhibited no ability to induce the activities of testosterone hydroxylations at positions 2 alpha, 6 beta and 7 alpha, benzo[a]pyrene 3-hydroxylation and aniline hydroxylation. In addition to the CYP2B P450, strychnine and brucine induced glutathione S-transferase toward 1-chloro-2,4-dinitrobenzene and UDP-glucuronosyltransferase toward 4-nitrophenol. On the other hand, the glucuronidations of 4-hydroxybiphenyl and morphine were not enhanced by alkaloid treatments. These results indicated that strychnine and brucine cause phenobarbital-like induction of the P450 enzyme, but show a different profile from phenobarbital in the induction of UDP-glucuronosyltransferase.
在大鼠中研究了两种生物碱士的宁和马钱子碱对肝脏药物代谢酶的诱导活性。给大鼠饮用含士的宁的水后，显著增加了苄非他明N-脱甲基、士的宁2-羟基化以及睾酮在16α和16β位羟基化的肝微粒体活性。这些结果连同微粒体蛋白免疫染色结果表明，士的宁是CYP2B1和2B2的有效诱导剂。用马钱子碱处理可观察到对CYP2B1/2的类似诱导作用，且毒性较小。虽然这种诱导剂在连续给药4天后使CYP2B细胞色素P450（P450）增加到最高水平，但士的宁在给药3天后达到最大增加量。免疫印迹实验表明，在士的宁和马钱子碱处理过程中，CYP2B1发生了显著的蛋白水解。这些生物碱没有诱导睾酮在2α、6β和7α位羟基化、苯并[a]芘3-羟基化以及苯胺羟基化活性的能力。除了CYP2B P450外，士的宁和马钱子碱还诱导了谷胱甘肽S-转移酶对1-氯-2,4-二硝基苯的活性以及UDP-葡萄糖醛酸基转移酶对4-硝基苯酚的活性。另一方面，生物碱处理并未增强4-羟基联苯和吗啡的葡萄糖醛酸化。这些结果表明，士的宁和马钱子碱引起了苯巴比妥样的P450酶诱导，但在UDP-葡萄糖醛酸基转移酶诱导方面表现出与苯巴比妥不同的特征。
