title: Lapachol inhibition of vitamin K epoxide reductase and vitamin K quinone reductase.
abstract: 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.
mesh_terms: D000818:Animals; D000925:Anticoagulants; D004229:Dithiothreitol / Q000494:pharmacology; D004351:Drug Resistance; D007700:Kinetics; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009285:Naphthoquinones / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011808:Quinone Reductases / Q000037:antagonists & inhibitors*; D051381:Rats; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D009285:Naphthoquinones; D014859:Warfarin; C008252:lapachol; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D009247:NADH, NADPH Oxidoreductases; D011808:Quinone Reductases; D004229:Dithiothreitol