Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase

Arch Biochem Biophys. 1984 Nov 1;234(2):405-12. doi: 10.1016/0003-9861(84)90286-8.


Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] has been shown to be a potent inhibitor of both vitamin K epoxide reductase and the dithiothreitol-dependent vitamin K quinone reductase of rat liver microsomes in vitro. These observations explain the anticoagulant activity of lapachol previously observed in both rats and humans. Lapachol inhibition of the vitamin K epoxide and quinone reductases resembled coumarin anticoagulant inhibition, and was observed in normal strain but not in warfarin-resistant strain rat liver microsomes. This similarity of action suggests that the lactone functionality of the coumarins is not critical for their activity. The initial-velocity steady-state inhibition patterns for lapachol inhibition of the solubilized vitamin K epoxide reductase were consistent with tight binding of lapachol to the oxidized form of the enzyme, and somewhat lower affinity for the reduced form. It is proposed that lapachol assumes a 4-enol tautomeric structure similar to that of the 4-hydroxy coumarins. These structures are analogs of the postulated hydroxyvitamin K enolate intermediate bound to the oxidized form of the enzyme in the chemical reaction mechanism of vitamin K epoxide reductase, thus explaining their high affinity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticoagulants
  • Dithiothreitol / pharmacology
  • Drug Resistance
  • Kinetics
  • Microsomes, Liver / enzymology*
  • Mixed Function Oxygenases / antagonists & inhibitors*
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • Naphthoquinones / pharmacology*
  • Oxidation-Reduction
  • Quinone Reductases / antagonists & inhibitors*
  • Rats
  • Vitamin K Epoxide Reductases
  • Warfarin / pharmacology


  • Anticoagulants
  • Naphthoquinones
  • Warfarin
  • lapachol
  • Mixed Function Oxygenases
  • Vitamin K Epoxide Reductases
  • NADH, NADPH Oxidoreductases
  • Quinone Reductases
  • Dithiothreitol