Evidence that warfarin anticoagulant action involves two distinct reductase activities.
The dithiothreitol-dependent vitamin K and vitamin K 2,3-epoxide hepatic microsomal reductase activities of warfarin-susceptible and warfarin-resistant rats were compared to gain insight into the role(s) of these activities in vitamin K metabolism and function. In microsomes from resistant rats, 3- to 4-fold more warfarin was required to produce 50% inhibition (I50) of vitamin K reduction to vitamin K hydroquinone than in microsomes from susceptible rats. For the reduction of vitamin K 2,3-epoxide to vitamin K a 6-fold higher warfarin concentration was required. In microsomes from resistant rats, the I50 warfarin concentration required to inhibit gamma-carboxylation of microsomal precursor protein was also 4-fold higher with vitamin K as substrate and was 6-fold higher with the epoxide as substrate than in microsomes from susceptible rats. Collectively, these data suggest that the vitamin K reductase contributes to the metabolism of vitamin K in intact rats and that warfarin inhibition of both the vitamin K and vitamin K 2,3-epoxide reductases is involved in its anticoagulant effect.
D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D004351:Drug Resistance; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases / Q000378:metabolism; D051381:Rats; D014812:Vitamin K / Q000378:metabolism; D014813:Vitamin K Deficiency / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology* / Q000627:therapeutic use
D014812:Vitamin K; D014859:Warfarin; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D016660:NAD(P)H Dehydrogenase (Quinone); D011808:Quinone Reductases; D004229:Dithiothreitol