MECHANISM OF ACTION OF ANTICOAGULANTS: CORRELATION BETWEEN THE INHIBITION OF PROTHROMBIN SYNTHESIS AND THE REGENERATION OF VITAMIN K1 FROM VITAMIN

REN, P., P. Y. STARK, R. L. JOHNSON AND R. G. BELL: Mechanism of action of anticoagulants: Correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K from vitamin K epoxide. J. Pharmacol. Exp. Ther. 201: 541-546, 1977. It has been proposed that coumarin and indandione anticoagulants inhibit clotting protein synthesis by preventing the regeneration of vitamin K from its 2,3-epoxide metabolite. To test this hypothesis, the effects of nine coumarmn and indandiones on prothrombin synthesis and the conversion of vitamin K, epoxide to vitamin K were measured. There was a good correlation between the inhibition of prothrombin synthe-sis and the epoxide-K conversion both in vivo and in vitro. Diphenadione (2-diphenyl acetyl-1,3-indandione) caused a delayed inhibition of prothrombin synthesis which correlated with a delayed inhibition of the epoxide-K, conversion in vivo. These results provide strong evidence for the proposed mechanism of action of coumarin and indan-dione anticoagulants. Recent work has demonstrated that vitamin K is necessary for the carboxylation of glutamic acid residues in a precursor protein (Stenflo, 1976). This produces biologically active pro-thrombin which contains y-carboxyglutamic acid. How vitamin K functions in the carboxy-lation and how anticoagulants antagonize its action are not known. Vitamin K-2,3-epoxide, the major metabo-lite of vitamin K in both rat and man, accumu-lates in the presence of coumarin and indan-dione anticoagulants (Matschiner et at. 1970; Ren et at., 1974; Shearer et at., 1974). Our origi-Received for publication November 17, 1976