Molecular Pharmacology, Vol 10, 373-380, Copyright © 1974 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Warfarin, Phenylindanedione, Tetrachloropyridinol, and Chloro-vitamin K₁ on Prothrombin Synthesis and Vitamin K Metabolism in Normal and Warfarin-Resistant Rats

¹ Biochemistry Department, University of Rhode Island, Kingston, Rhode Island 02881

Anatagonists of vitamin K—warfarin, phenylindanedione the 2-chloro analogue of vitamin K₁, and tetrachloropyridinol—blocked prothrombin synthesis completely and without a lag period in the rat. Experiments to determine the mode of action of the antagonists indicated that they could be divided into two groups. The inhibition of prothrombin synthesis by all four antagonists was reversed by vitamin K₁, but the inhibition in Sprague-Dawley rats by group I (warfarin and phenylindanedione) was not reversed by phylloquinone epoxide, beause the group I compounds inhibited the conversion of [³H] phylloquinone epoxide to the active vitamin, [³H]vitamin K₁, and caused the accumulation of [³H] phylloquinone epoxide in rats that had received injections of the tritiated vitamin. It is proposed that group I compounds were ineffective in blocking prothrombin synthesis in warfarin-resistant rats because in these animals the conversion from epoxide to K₁ is not as sensitive as in normal animals. Consequently the epoxide can stimulate prothrombin synthesis in the presence of group I compounds in the resistant strain. In contrast, the inhibition of prothrombin synthesis by group II (tetrachloropyridinol and 2-chloro-vitamin K₁) was reversed by epoxide, because these compounds inhibited the [³H] phylloquinone epoxide to [³H] vitamin K₁ conversion much less than those of group I. Similarly, the effect of group II on the metabolism of [³H] vitamin K₁ was much smaller than that of group I. Group II compounds blocked prothrombin synthesis in warfarin-resistant animals at least as well as in Sprague-Dawley rats. These results are consistent with the idea that coumarin and indanedione anticoagulants (group I) inhibit prothrombin synthesis by causing the accumulation of an inhibitor of the vitamin, phylloquinone epoxide, and that 2-chloro-vitamin K₁ and tetrachloropyridinol (group II) act at another site.

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ACKNOWLEDGMENTS The authors wish to acknowledge the invaluable technical assistance of Ms. Deborah Chisholm, Ms. Laurel Truesdell, and Mr. Paul Caldwell.