Further studies on the regulation of human placental steroid 3-sulfatase activity.

Abstract

Previously, we have proposed that inhibition of human placental steroid sulfatase by endogenous steroids may render it rate limiting and provide a mechanism controlling estrogen synthesis from C19-Δ5-3β-yl sulfates during pregnancy. Inhibitory effects of 129 endogenous and synthetic steroids on DHAS (l7-oxo-5-androsten- 3β-yl sulfate, apparent Km = 3.3 × 10-5M) hydrolysis by human term placental sulfatase have now been determined in vitro. Structure-activity data are compatible with binding of conjugated steroids to the enzyme via 3 sites, in addition to hydrophobic interactions. Inhibitory activity of unconjugated compounds is favored by planar Δ5-or 5α-structures unsubstituted except for oxygen functions at C-3 and C-20. Alternative substrates (e.g., pregnenolone sulfate, apparent Ki = 0.06 × 10-5M), acting competitively, were the most potent inhibitors. They appear to be the major potential factors reducing effective sulfatase levels in the proposed mechanism. Cumulative effects of other endogenous, co...