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Application of Chemical Cytochrome P-450 Model System to Studies on Drug Metabolism.

化学细胞色素P-450模型系统在药物代谢研究中的应用。

基本信息

批准号：
02453140
负责人：
HIROBE Masaaki
金额：
$ 4.93万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

Cytochrome P-450 plays an important role in metabolizing biomolecules and xenobiotics, and the mechanism of its catalytic activities has been the subject of extensive investigation. Recently many attempts have been made to reproduce the reactivity in chemical systems with a simple metalloporphyrin. We have achieved the synthesis of many effective P-450 mimics and clarified their functions with the aim of developing artificial enzymes having high similarity to the native P-450 system for investigation of drug metabolism.Here we present the results of our studies for three years.(1) The stable iron porphyrin ligated by alkyl thiolate showed enormously accelerated heterolytic O-O bond cleavage of peracids even in hydrophobic solvents. The heterolytic cleavage gives Fe^<5+>-oxenoid type active species which is thought to be a strong oxidant.(2) Modified cytochrome c, immobilized cytochrome c and microperoxidase-11, catalyzed some P-450-like substrate oxidations. The reaction mechanisms of these N- and S-oxidations were similar to those of P-450itself.(3) Ru-porphyrin/2,6-disubstituted pyridine N-oxide system was developed for olefin epoxidation. In the presence of acid, this system effectively catalyzed a oxidation of unactivated alkane and turn over number of the catalyst was 18800.(4) Many P-450 model systems were tested for ability to metabolize various drugs compared with the native P-450 system and coupling reactions of aniline derivatives, beta-oxo formation of piperidine derivatives, and oxidative decarboxylation of phenylacetic acid derivatives were found to be new P-450 dependent metabolic pathways. These results clearly show that P-450 model is useful for identification of minor/new/unstable metabolites.

细胞色素P-450在生物分子和外源物质的代谢中起着重要作用，其催化活性的机制一直是广泛研究的主题。近年来，人们尝试用简单的金属卟啉来再现化学体系中的反应性。为了开发与天然P-450系统具有高度相似性的人工酶用于药物代谢研究，我们合成了许多有效的P-450模拟物，并阐明了它们的功能。(1)通过烷基硫醇配位的稳定铁卟啉显示出即使在疏水溶剂中也极大地加速了过酸的异裂O-O键断裂。异裂裂解产生Fe^<5+>-oxenoid型活性物种，其被认为是强氧化剂。(2)修饰的细胞色素c，固定化细胞色素c和微过氧化物酶-11，催化一些P-450样底物氧化。这些N-和S-氧化的反应机理与P-450本身的反应机理相似。(3)研究了钌卟啉/2，6-二取代吡啶N-氧化物体系催化烯烃环氧化反应。在酸存在下，该体系有效地催化未活化烷烃的氧化，催化剂的转化数为18800。(4)许多P-450模型系统进行了测试的能力，代谢各种药物相比，自然P-450系统和苯胺衍生物的偶联反应，β-氧代形成哌啶衍生物，苯乙酸衍生物的氧化脱羧被发现是新的P-450依赖性代谢途径。这些结果清楚地表明，P-450模型可用于鉴别次要/新/不稳定代谢物。