Inhibition of rat alpha-reductases by finasteride: evidence for isozyme differences in the mechanism of inhibition

J Steroid Biochem Mol Biol. 1997 Apr;61(1-2):55-64. doi: 10.1016/s0960-0760(97)00002-2.

Abstract

The mechanism of inhibition of the rat types 1 and 2 5alpha-reductase by finasteride was investigated using recombinantly expressed enzymes. These studies revealed that finasteride is a potent, reversible inhibitor of the rat type 1 5alpha-reductase with Ki=10.2+/-1.3 nM. Finasteride is a potent inhibitor of the rat type 2; however, in this case the compound binds to the type 2 isozyme-NADPH complex to form a ternary complex with Ki=1.19+/-0.10 nM, which then rearranges to a high affinity complex (E:I) with a pseudo first order rate constant of 1.62+/-0.22 x 10(-3)/s. The second order rate constant is k3/Ki=1.37+/-0.31 x 10(6) M/s. Heat denaturation of the (type 2 enzyme:inhibitor) complex releases dihydrofinasteride and presumably the NADP+-adduct previously identified with the human 5alpha-reductases. The effects of finasteride were also studied in intact COS cells transiently expressing the rat types 1 and 2 5alpha-reductase. Results with whole cell assays confirm differences in mechanism of inhibition of rat types 1 and 2 5alpha-reductase by finasteride.

MeSH terms

  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • 5-alpha Reductase Inhibitors*
  • Animals
  • COS Cells
  • Enzyme Inhibitors / pharmacology
  • Finasteride / pharmacology*
  • Hot Temperature
  • Isoenzymes / antagonists & inhibitors*
  • Kinetics
  • NADP / metabolism
  • Protein Denaturation
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Fusion Proteins

Substances

  • 5-alpha Reductase Inhibitors
  • Enzyme Inhibitors
  • Isoenzymes
  • Recombinant Fusion Proteins
  • NADP
  • Finasteride
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase