Studies on aromatase inhibition with 4-androstene-3,6,17-trione: its 3 beta-reduction and time-dependent irreversible binding to aromatase with human placental microsomes.
The metabolism of 4-androstene-3,6,17-trione (AT), previously described as a suicide substrate for aromatase, and its irreversible binding to aromatase were studied by using human placental microsomes. AT was rapidly converted into 3 beta-reduced metabolite (3-OHAT) with an enzyme other than aromatase in the microsomes in the presence of NADPH under either aerobic or anaerobic conditions. The conversion was efficiently prevented by a steroid 5 alpha-reductase inhibitor. 3-OHAT was characterized as a competitive (Ki = 6.5 microM) and irreversible inhibitor of aromatase. Both 14C-labeled AT and 3-OHAT were demonstrated to be irreversibly bound to aromatase probably through a sulfur atom of the enzyme in time-dependent manners in the presence of NADPH, being accompanied with time-dependent losses of the enzyme activity. It was shown that the process of an apparent time-dependent loss of aromatase activity caused by AT even under conditions allowing its 3 beta-reduction should principally depend on the action of the parent inhibitor AT itself and not on that of the metabolite 3-OHAT.
Numazawa
M
M
Tohoku College of Pharmacy, Sendai, Japan.
Tsuji
M
M
Mutsumi
A
A
D000736:Androstenes / Q000378:metabolism / Q000494:pharmacology*; D047072:Aromatase Inhibitors; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology*; D010084:Oxidation-Reduction; D010920:Placenta / Q000201:enzymology*; D011485:Protein Binding; D013997:Time Factors
D000736:Androstenes; D047072:Aromatase Inhibitors; C011657:adrenosterone