title: Indirect inhibition of vitamin K epoxide reduction by salicylate.
abstract: Salicylate antagonizes the vitamin K-dependent biosynthesis of clotting factors in the rat and produces an elevation of the ratio of vitamin K epoxide to vitamin K in the liver. Vitamin K epoxide is reduced to vitamin K by a vitamin K epoxide reductase, and 1 mM salicylate was required to cause a 50% inhibition of the dithiothreitol-dependent in-vitro reduction of vitamin K epoxide by this enzyme. This enzyme was, however, inhibited 50% by as little as 70-80 microM salicylate when reducing equivalents for the reaction were furnished by endogenous cytosolic reductants. This effect on the cytosolic reductant supply was shown to be unrelated to a previously demonstrated inhibition of DT-diaphorase by salicylate. The concentrations of salicylate at which significant inhibitory effects are exerted in-vitro (50-100 microM) are below the 200 microM levels observed in the livers of rats given an anticoagulating dose of salicylate.
mesh_terms: D000818:Animals; D003600:Cytosol / Q000201:enzymology; D008058:Dihydrolipoamide Dehydrogenase / Q000037:antagonists & inhibitors; D004229:Dithiothreitol / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D012459:Salicylates / Q000494:pharmacology*; D020156:Salicylic Acid; D013989:Ticrynafen / Q000494:pharmacology; D010837:Vitamin K 1 / Q000031:analogs & derivatives* / Q000378:metabolism; D064417:Vitamin K Epoxide Reductases
chemical_list: D012459:Salicylates; C016186:vitamin K1 oxide; D010837:Vitamin K 1; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D008058:Dihydrolipoamide Dehydrogenase; D013989:Ticrynafen; D020156:Salicylic Acid; D004229:Dithiothreitol