Studies of the time-dependent inactivation of aromatase by 4beta,5beta-epoxy-6-one and 5beta,6beta-epoxy-4-one steroids under various conditions.
The time-dependent inactivation of aromatase by epoxy analogs of the good aromatase inhibitors, androst-4-ene-6,17-dione (3) and androst-5-ene-4,17-dione (7), 4beta,5beta-epoxy and 5beta,6beta-epoxy compounds 10 and 13 and their 19-oxo derivatives 11 and 14, was examined in either the presence or absence of NADPH. The 4beta,5beta-epoxy-19-oxo steroid 11 along with the 19-methyl-5beta,6beta-epoxide 13 inactivated human placental aromatase in a mechanism-based manner, in the presence of NADPH, with rate constants for inactivation (k(inact)) of 0.133 min(-1) for steroid 11 and 0.100 min(-1) for steroid 13, whereas the two other steroids, 10 and 14, did not. On the other hand, none of four epoxides studied caused time-dependent inactivation of aromatase in an affinity-labeling manner in the absence of NADPH. These results are the first report showing that inhibitors 11 and 13 are suicide substrates having an epoxyketone structural feature.
Numazawa
M
M
Tohoku Pharmaceutical University, Aobaku, Sendai, Japan.
Yamada
K
K
D000735:Androstenedione / Q000494:pharmacology; D047072:Aromatase Inhibitors; D003545:Cysteine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009249:NADP / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D013237:Stereoisomerism; D013256:Steroids / Q000494:pharmacology*; D013997:Time Factors
D047072:Aromatase Inhibitors; D004791:Enzyme Inhibitors; D013256:Steroids; D000735:Androstenedione; D009249:NADP; D003545:Cysteine