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Human prostatic steroid 5 alpha-reductase isoforms--a
comparative study of selective inhibitors.
AUTHOR
Iehlé C; Délos S; Guirou O; Tate R; Raynaud JP; Martin
PM
JOURNAL
J Steroid Biochem Mol Biol, 54: 5-6, 1995 Sep, 273-9
ABSTRACT
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 (Km = 0.5 and 2.9 microM,
respectively). Finasteride and turosteride were selective inhibitors
of the type 2 isoform (Ki (type 2) = 7.3 and 21.7 nM compared to
Ki (type 1) = 108 and 330 nM, respectively). 4-MA and the lipido-sterol
extract of Serenoa repens (LSESr) markedly inhibited both isozymes
(Ki (type 1) = 8.4 nM and 7.2 micrograms/ml, respectively; Ki (type
2) = 7.4 nM and 4.9 micrograms/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 alpha-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.
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