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Analysis of Interaction between Cytochrome P-450 and Antifungal Agents

细胞色素 P-450 与抗真菌药物的相互作用分析

基本信息

批准号：
61571076
负责人：
YOSHIDA YUZO Ph.D.
金额：
$ 1.15万
依托单位：
Mukogawa Women's University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1986
资助国家：
日本
起止时间：
1986 至 1987
项目状态：
已结题

项目摘要

Molecular mechanism of interaction between cytochrome P450 and azole antifungal agents that interfere with the fungal sterol bio-synthesis was studied by using purified preparation of cytochrome P450/14DM (lanosterol 14-demethylase) of yeast.Azole antifungal agents avidly bind to cytochrome P450/14DM and inhibited the lanosterol demethylase activity of the cytochrome. This finding confirmed the proposed mechanism of action of the anti-fungal agents that their antifungal action might be due to depretion of ergosterol and accumulation of 14-methylsterols.By comparing affinities of various antifungal agents for cyto-chrome P450/14DM with one another, the structures necessary for interaction with the cytchrome could be deduced. This finding provided fundamental concept for structure-function relationship of azole antifungal agents.By comparing affinities and inhibitory effects of enantiomers of optically active antifungal agents, it was found that only one enantiomer interacted with cytochrome P450/14DM with extremely high affinity. This finding indicated that assesment of the inhibitory effects of individual enantiomers on cytochrome P-450/14DM should be important for developing more improved azole antifungal agents.The antifungal agents which showed relatively low affinity for the yeast enzyme inhibited both the yeast and rat liver enzymes at nearly the same concentration. On the other hand, it was found that the azole antifungal agents that interacted with yeast cytochrome P450/14DM with very high affinity showed some selectivity for the yeast enzyme.

利用酵母细胞色素P450/14 DM（lanosterol 14-demethylase，羊毛甾醇14-脱甲基酶）的纯化制剂，研究了细胞色素P450与唑类抗真菌剂相互作用的分子机制，唑类抗真菌剂与细胞色素P450/14 DM结合，抑制细胞色素P450/14 DM的羊毛甾醇脱甲基酶活性。这一发现证实了抗真菌药物的抗真菌作用可能是由于麦角甾醇的降解和14-甲基甾醇的积累.通过比较各种抗真菌药物与细胞色素P450/14 DM的亲和力，可以推断出与细胞色素相互作用所必需的结构.通过比较光学活性抗真菌药物对映体的亲和性和抑菌效果，发现只有一种对映体与细胞色素P450/14 DM具有极高的亲和性。这一发现表明，评价单个对映体对细胞色素P-450/14 DM的抑制作用对于开发更好的唑类抗真菌剂是重要的，对酵母酶表现出相对低亲和力的抗真菌剂在几乎相同的浓度下对酵母和大鼠肝酶都具有抑制作用。另一方面，发现与酵母细胞色素P450/14 DM以非常高的亲和力相互作用的唑类抗真菌剂对酵母酶表现出一定的选择性。