精製チトクロームP-45011β触媒反応に及ぼす副腎ステロイド生成阻害剤の作用:Ketoconazoleを中心に

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Keroconazole (Nizoral), an orally active antimycotic agent with a broad spectrum, has been reported to interfere with steroidogenesis both in patient and in vivo rat studies. It has also been shown that the same drug inhibits some P-450-catalyzed reactions in adrenal cortex mitochondria. In the present work, we studied the inhibitory effect of Ketoconazole, along with some other known inhibitors of steroidogenesis, on the reconstituted steroid monooxygenase system, which consists of adrenodoxin, its reductase and P-45011β as the protein components being purified from bovine adrenal cortex mitochondria. The results indicated that; 1) Ketoconazole completely inhibited hyroxylation of deoxycorticosterone at the 11β position to form corticosterone and at the 18-position to form 18-hydroxydeoxycorticosterone. The Ki value for Ketoconazole, calculated either from the 11β-hydroxylase reaction or the 18-hydroxylase reaction, was 0.56 μM, which was comparable to the value obtained for metyrapone in the same system. 2) Ketoconazole also inhibited 18-hydroxylation of corticosterone to form 18-hydroxycorticosterone, with 50% inhibitory concentration of less than 0.03 μg/ml. The corresponding value for this inhibitor in the deoxycorticosterone 18-hydroxylase reaction was found to be 0.3 μg/ml. The contrast between these values for the two substrates is striking. Thus, in a series of reaction steps, the inhibitory effect of corticosterone to 18-hydroxycorticosterone was more potent than deoxycorticosterone to 18-hydroxycorticosterone reaction. 3) Both trilostane and o, p ' -DDD over the wide concentration range failed to inhibit any of the reconstituted P-45011β system similar to those applied to the Ketoconazole study. NADPH-adrenodoxin reductase activity was not inhibited by either of these drugs, indicating both Trilostane and o, p'-DDD had no significant effect on the purified-reconstituted P-45011β system.
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精製チトクロームP-450<SUB>11β</SUB>触媒反応に及ぼす副腎ステロイド生成阻害剤の作用:Ketoconazoleを中心に

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