Evidence that warfarin anticoagulant action involves two distinct reductase activities.

作者：Michael J. Fasco, Ellen F. Hildebrandt, John W. Suttie · 发表于：Journal of Biological Chemistry · 年份：1982 · DOI：10.1016/s0021-9258(18)33742-6 · 被引用次数：164 · 研究领域：Vitamin K Research Studies、Pharmacogenetics and Drug Metabolism、Vitamin C and Antioxidants Research

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.