肝ミクロソームの酸化的薬物代謝酵素(チトクロムP-450)系に対する合成ステロイド剤・Danazolの阻害作用

概要

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The inhibitory effect of danazol, a synthetic androgen, on the hydroxylations of testosterone as a model for endogenous steroids and the dealkylations of aminopyrine and 7-ethoxycoumarin as models for xenobiotics in mouse hepatic microsomes in vitro was studied. Danazol inhibited these enzyme activities in a dose-dependent fashion. The inhibition constants (K_1) of danazol for these enzyme activities were 1-4 orders of magnitude lower than those of cimetidine, while there was a great difference among the inhibitory potencies of danazol for each enzyme activity. Addition of danazol to microsomal preparation resulted in a reverse type I difference spectrum and the spectrophotometric analysis revealed that danazol had a high affinity for cytochrome P-450 with dissociation constants (K_9) of 0.9 and 4.2 μM, which were 2 orders of magnitude lower than those of cimetidine. On the other hand, danazol did not significantly affect reduced nicotinamide adenine dinucleotide phosphate cytochrome c reductase activity and levels of cytochrome P-450 in the microsomes. These results suggest that danazol is a highly potent inhibitor for several cytochrome P-450-mediated metabolisms of testosterone and xenobiotics in mouse hepatic microsomes.
公益社団法人日本薬学会の論文
1990-01-25