The constitutive 7-ethoxycoumarin 0-deethylase of human placental microsomes: relationship to the intermediary steps in steroid aromatization

Abstract

All oxidative functions of aromatase, i.e., estrogen production, 19-oxygenated androgen production and 7-ethoxycoumarin deethylation, were inhibited in parallel in placental microsomes from non-smokers by the mechanism-based, time-dependent inactivators (suicide substrates) 10β-(2-propynyl)estr-4-ene-3, 17-dione and 4-hydroxyandrost-4-ene-3, 17-dione. In contrast, the aromatase suicide substrate androst-4-ene-3, 6, 17-trione had little or no effect on the conversion of androst-4-ene-3, 17-dione to 19-hydroxyandrost-4-ene-3, 17-dione or on the conversion of the latter to 3, 17-dioxoandrost-4-en-19-al while severely limiting the capacity for estrogen production from androst-4-ene-3, 17-dione and 19-hydroxyandrost-4-ene-3, 17-dione in such microsomal preparations. Androst-4-ene-3, 6, 17-trione, therefore, appears to uncouple the 19-hydroxylation of androgens from estrogen synthesis. This agent also produced only a minimal inhibition of 7-ethoxycoumarin deethylation, indicating that this major constitutive transformation of a xenobiotic chemical is associated with the steroid 19-hydroxylating function of the aromatase system.