Human prostatic steroid 5 alpha-reductase isoforms--a comparative study of selective inhibitors

Catherine Iehlé, Sylvie Délos, Olivier Guirou, Rothwell Tate, Jean-Pierre Raynaud, Pierre-Marie Martin

Research output: Contribution to journalArticle

110 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)273-279
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume54
Issue number5-6
DOIs
Publication statusPublished - 30 Sep 1995

Keywords

  • animals
  • azasteroids
  • Cholestenone 5 alpha-Reductase
  • dihydrotestosterone
  • enzyme activation
  • enzyme inhibitors
  • finasteride
  • insects
  • isoenzymes
  • oxidoreductases
  • prostate
  • recombinant proteins
  • transfection

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