Studies of the inactivation of human placental aromatase by 17 alpha-ethynyl-substituted 10 beta-hydroperoxy and related 19-nor steroids.
The inactivation of human placental aromatase by 17 alpha-ethynyl-10 beta-hydroperoxy-17 beta-hydroxy-4-estren-3-one (SCH 10015) was investigated. In either the presence or absence of added NADPH, SCH 10015 (Ki = 41 microM) caused a time-dependent loss of aromatase activity (e.g. 50% loss after 20 min with 20 microM SCH 10015). Evidence for the oxidation of an active site sulfhydryl group as the molecular basis for SCH 10015 inactivation is presented. The contraceptive 17 alpha-ethynyl-substituted 19-nor steroids, norethisterone (Ki = 48 microM) and norethynodrel (Ki = 38 microM), were evaluated and found not to inactivate aromatase, suggesting that the potential conversion of either compound to SCH 10015 did not occur to a significant extent in these microsomal incubations. It is speculated that the previously observed potent contraceptive effects of SCH 10015 may have been the result of irreversible inhibition of estrogen biosynthesis.
Covey
D F
DF
Hood
W F
WF
McMullan
P C
PC
D047072:Aromatase Inhibitors; D005260:Female; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D009640:Norethindrone / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D013256:Steroids / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D013256:Steroids; D009640:Norethindrone