Four-amino acid segment in steroid 5α-reductase 1 confers sensitivity to finasteride, a competitive inhibitor

Anice E. Thigpen, David W. Russell

Research output: Contribution to journalArticlepeer-review

88 Scopus citations


The 4-azasteroid 17β-(N-t-butyl)carbamoyl-4-aza-5α-androst-1-en-3-one (finasteride) is 100-fold more potent as a competitive inhibitor of the rat NADPH:Δ4-3-oxosteroid-5α-oxidoreductase (steroid 5α-reductase) type 1 enzyme (K(i) = 3-5 nM) than of the human type 1 enzyme (K(i) ≥ 300 nM). In this study, we exploit this differential sensitivity to map a major determinant of finasteride sensitivity in steroid 5α-reductase. Chimeric steroid 5α-reductase cDNAs composed of different combinations of rat and human exon sequences were created by genetic engineering, expressed in human embryonic kidney 293 cells, and assayed for their sensitivity to finasteride. Hybrid proteins containing sequences encoded by rat exon 1 were found to be as sensitive to finasteride as the parental enzyme. The exchange of progressively smaller protein segments encoded within exon 1 identified a tetrapeptide sequence (Val-Ser-Ile-Val) in the rat enzyme that conferred sensitivity to finasteride. The analogous sequence in the human enzyme (Ala- Val-Phe-Ala) conferred partial resistance to the drug. Finasteride was a competitive inhibitor of the native and all chimeric enzymes tested, suggesting that the tetrapeptide segments form a portion of the substrate- binding domain of steroid 5α-reductase.

Original languageEnglish (US)
Pages (from-to)8577-8583
Number of pages7
JournalJournal of Biological Chemistry
Issue number12
StatePublished - 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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