Citation

Numazawa M, Tachibana M. Steroids 1997; 62(7): 516-522.

Copyright

(Copyright © 1997, Elsevier Publishing)

DOI

10.1016/s0039-128x(97)00002-0

PMID

9253790

Abstract

To gain further insight into the mechanism for inactivation of aromatase by androst-5-ene-7,17-dione (1) and its 19-nor analog 4, 10 beta-oxygenated steroids 5 and 6, delta 1(10)-steroid 7, and 19-oxo-5 beta,6 beta-epoxy compound 8 were synthesized and tested for their ability to inhibit aromatase in human placental microsomes. All of the steroids studied inhibited the enzyme in a competitive manner with apparent Ki values ranging from 1.1 to 35 microM. The delta 1(10)-compound 7 was the most potent inhibitor among them. All of the inhibitors caused a time-dependent inactivation of aromatase in the presence of NADPH in air with the kinact values ranging from 0.036 to 0.190 min-1. The substrate androstenedione protected the inactivation, but a nucleophile, L-cysteine, did not, in each case. In contrast, each inhibitor did not cause the time-dependent inactivation in the absence of NADPH. These results show that the 5 beta,6 beta-epoxide 8 and/or the dienone 7 are not a reactive electrophile involved in the irreversible binding to the active site of aromatase during the mechanism-based inactivation caused by the suicide substrates 1 and/or 4.

Language: en

Keywords

Androstanes; Androstenedione; Aromatase; Aromatase Inhibitors; Binding, Competitive; Enzyme Inhibitors; Female; Humans; Kinetics; NADP; Placenta; Pregnancy; Structure-Activity Relationship; Time Factors