HUMAN PROSTATIC STEROID 5-ALPHA-REDUCTASE ISOFORMS - A COMPARATIVE-STUDY OF SELECTIVE INHIBITORS

The present study describes the independent expression of the type 1 and 2 isoforms of human 5 alpha-reductase in the baculovirus-directed insect cell expression system and the selectivity of their inhibition. The catalytic properties and kinetic parameters of the recombinant isozymes were consistent with published data. The type 1 isoform displayed a neutral (range 6-8) pH optimum and the type 2 isoform an acidic (5-6) pH optimum. The type 2 isoform had higher affinity for testosterone than did the type 1 isoform (K-m = 0.5 and 2.9 mu M, respectively). Finasteride and turosteride were selective inhibitors of the type 2 isoform (K-i (type 2) = 7.3 and 21.7 nM compared to K-i (type 1) = 108 and 330 nM, respectively). 4-MA and the lipido-sterol extract of Serenoa repens (LSESr) markedly inhibited both isozymes (K-i (type 1) = 8.4 nM and 7.2 mu g/ml, respectively; K-i (type 2)= 7.4 nM and 4.9 mu g/ml, respectively). The three azasteroids were competitive inhibitors vs substrate, whereas LSESr displayed non-competitive inhibition of the type 1 isozyme and uncompetitive inhibition of the type 2 isozyme. These observations suggest that the lipid component of LSESr might be responsible for its inhibitory effect by modulating the membrane environment of 5 alpha-reductase. Partially purified recombinant 5(a)lpha-reductase type 1 activity was preserved by the presence of lipids indicating that lipids can exert either stimulatory or inhibitory effects on human 5 alpha-reductase.