Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes
Metabolism and metabolic inhibition of gambogic acid in rat liver microsomes
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DOI：
10.1111/j.1745-7254.2006.00369.x
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发表时间：
2006-09-01
影响因子：
8.2
通讯作者：
Wang, Guang-ji
中科院分区：
文献类型：
--
作者：
Liu, Yi-tong;Hao, Kun;Wang, Guang-ji
目的：研究体外培养的大鼠肝微粒体中γ-氨基丁酸(GA)的代谢及选择性细胞色素P-450(CYP450)抑制剂对GA代谢的影响。方法：采用大鼠肝微粒体法进行代谢研究。用不同的选择性细胞色素P450抑制剂研究了它们对GA代谢的影响，以及参与大鼠肝微粒体主要代谢产物M-1形成的主要细胞色素P450异构体。酶动力学模型中的抑制类型被用来模拟相互作用。结果：GA在大鼠肝微粒体中迅速代谢为两个I相代谢产物M-1和M-2。初步推测M-1为赤霉素A的水合代谢产物，M-2为赤霉素A的环氧化代谢物。α-萘黄酮非竞争性抑制M-1的形成，而酮康唑、磺胺苯唑、二乙基二硫代氨基甲酸酯和奎尼丁对M-1的形成几乎没有抑制作用。结论：GA在大鼠肝微粒体中代谢迅速，M-1对GA的消除起关键作用。细胞色素P-4501A2是参与GA代谢的主要细胞色素P4501A2。
Aim: To study the metabolism of gambogic acid (GA) and the effects of selective cytochrome P-450 (CYP450) inhibitors on the metabolism of GA in rat liver microsomes in vitro. Methods: Rat liver microsomes were used to perform metabolism studies. Various selective CYP450 inhibitors were used to investigate their effects on the metabolism of GA and the principal CYP450 isoform involved in the formation of major metabolite M-1 in rat liver microsomes. Types of inhibition in an enzyme kinetics model were used to model the interaction. Results: GA was rapidly metabolized to two phase I metabolites, M-1 and M-2 in rat liver microsomes. M-1 and M-2 were tentatively presumed to be the hydration metabolite and epoxide metabolite of GA, respectively. alpha-Naphthoflavone uncompetitively inhibited the formation of M-1 while ketoconazole, sulfaphenazole, diethyl dithiocarbamate and quinidine had little or no inhibitory effects on the formation of M-1 Conclusion: GA is rapidly metabolized in rat liver microsomes and M-1 is crucial for the elimination of GA. Cytochrome P-450 1A2 is the major rat CYP involved in the metabolism of GA.