Analysis of Interaction between Cytochrome P-450 and Antifungal Agents
| Project/Area Number |
61571076
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Mukogawa Women's University |
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Principal Investigator |
YOSHIDA YUZO Ph.D. Faculty of Pharmaceutical Sciences, Mukogawa Women's University, 薬学部, 助教授 (70085281)
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| Co-Investigator(Kenkyū-buntansha) |
AOYAMA YURI Ph.D. Faculty of Pharmaceutical Sciences, Mukogawa Women's University, 薬学部, 助手 (00158718)
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| Project Period (FY) |
1986 – 1987
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| Project Status |
Completed (Fiscal Year 1988)
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| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1987: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1986: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | antifungal agent / sterol biosynthesis inhibitor / cytochrome P450 / optical isomer / enantiomer / 抗真菌剤 / 肝ミクロゾーム / ステロール生合成 / 薬物酸化酵素の阻害 / チトクロムP-450 / ステロール代謝 / ケトコナゾール / 酵母 / ラノステロール脱メチル化 / アゾール |
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| Research Abstract |
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.
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Report
(3 results)
Research Products
(22 results)
