ENZYME-GENERATED INTERMEDIATES DERIVED FROM 4-ANDR0STENE-3,6,17-TRI0NE AND 1,4,6-ANDR0STATRIENE-3,17-DI0NE CAUSE A TIME-DEPENDENT DECREASE IN HUMAN PLACENTAL AROMATASE ACTIVITY

Abstract

Kinetic evidence is presented for a time-dependent decrease in human placental aromatase activity by enzyme-generated intermediates derived from two widely used steroids previously described as competitive inhibitors of estrogen biosynthesis. Thus, 4-androstene-3,6,17-trione binds to the enzyme with an apparent of 0.43 pM and has a pseudo-first order overall rate constant for decrease in activity of 4.03×10^-3sec^-1 while 1,4,6-androstatriene-3,17-dione has an apparent K_ii of 0.18 μM and a pseudo-first order overall rate constant for decrease in activity of 1.10×10^-3sec^-1. These findings imply that the potent inhibition of estrogen biosynthesis caused by these steroids results primarily from a decrease in enzyme activity caused by enzyme–generated intermediates derived from the parent steroids.