[Inhibition of cytochrome P-450-dependent monoxygenase activities by a synthetic androgen danazol in mouse hepatic microsomes].
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 (Ki) 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 (Ks) of 0.9 and 4.2 microM, 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.
Konishi
H
H
Hospital Pharmacy, Shiga University of Medical Science, Ohtsu, Japan.
Morita
K
K
Ono
T
T
Shimakawa
H
H
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003613:Danazol / Q000494:pharmacology*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D010105:Oxygenases / Q000378:metabolism*; D011245:Pregnadienes / Q000494:pharmacology*
D011245:Pregnadienes; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; D003613:Danazol