Synthesis and destruction of prothrombin in the rat

Abstract

The kinetics of synthesis and destruction of prothrombin in the rat were investigated. In normal rats given cycloheximide or vitamin K antagonists, prothrombin activity declined logarithmically with half-lives ranging from 5.3 to 7.0 hr. The rate of prothrombin inactivation was slightly higher in vitamin K-deficient rats but did not increase with increasing severity of deficiency. The initial response to vitamin K by deficient rats was more rapid than predicted by the theoretical induction curve calculated from the rate of prothrombin destruction. After 1 hr the rate of prothrombin increase was similar to the theoretical rate and required over 15 hr to reach normal prothrombin concentration. In deficient rats given vitamin K in the presence of cycloheximide, a small rise in prothrombin activity was observed whereas in deficient rats given warfarin or the chloro analog of vitamin K response to vitamin K was obliterated. Actinomycin D administered to deficient rats up to 10 hr before vitamin K did not alter response to the vitamin. If the antibiotic was administered to normal rats, the prothrombin level was little changed for 10 hr after which it decreased with a half-life similar to that observed in rats treated with cycloheximide. The effect of actinomycin D on prothrombin concentration in deficient rats was similar to that observed in normal animals. From the data presented in this report we conclude that the inhibition of prothrombin destruction is not the principal mechanism of action of vitamin K. The more rapid than expected appearance of prothrombin in the plasma after the injection of vitamin K into deficient rats suggests that an unsteady state is established at the outset of the action of the vitamin. This could be due to (1) the release of small amounts of stored prothrombin, (2) the completion of a stored prothrombin precursor (on or off ribosomes), (3) the activation of stored or accumulated mRNA for prothrombin biosynthesis. Although de novo protein synthesis appears to be ultimately involved in the maintenance of plasma prothrombin levels under the influence of vitamin K, quantitative studies of the degree of labeling of plasma prothrombin during the initiation of vitamin K action will be required to determine the extent to which vitamin K itself participates in the biosynthesis of prothrombin.