Abstract
The role of vitamin K in the synthesis of prothrombin has been examined with the following results. 1. Vitamin K deficiency has no effect on general protein synthesis as studied by amino acid incorporation into protein in vivo and in vitro and by tryptophan pyrrolase production following tryptophan feeding. 2. Prothrombin activity was found in normal rat liver microsomes with increased release following ultrasonic treatment, but could not be found in microsomes from the livers of vitamin K-deficient rats or dicumarol-treated rats. Administration of suboptimal levels of vitamin K to vitamin K-deficient rats resulted in detectable microsomal prothrombin in 2 hours and essentially normal values within 3 hours. 3. Adequate vitamin K1, given by injection, completely restored the blood prothrombin levels of vitamin K-deficient rats in 1 hour, and of dicumarol- or warfarin-treated rats in 5 to 7 hours depending on the amounts of warfarin and vitamin K1 given. 4. Following administration of actinomycin D or ethionine to vitamin K-deficient rats, treatment with vitamin K1 markedly stimulated prothrombin production, indicating that the site of action of vitamin K is beyond the level of transcription of DNA to prothrombin messenger RNA. 5. Treatment with vitamin K1, following administration to vitamin K-deficient rats of cycloheximide at a level just sufficient to block synthesis of prothrombin for 6 to 8 hours, gave an essentially normal prothrombin response. At higher cycloheximide levels the response to vitamin K1, while much less complete, was clear and definite. 6. The response of vitamin K-deficient rats to vitamin K1, administered following treatment with blocking doses of puromycin, appears significant. 7. These data appear to indicate that the site of function of vitamin K is not at the genetic level, as has been reported, but at a late stage in translation of prothrombin messenger RNA to form a functional prothrombin molecule.
Highlights
Adequate vitamin KI, given by injection, completely restored the blood prothrombin levels of vitamin K-deficient rats in 1 hour, and of dicumarol- or warfarin-treated rats in 5 to 7 hours depending on the amounts of warfarin and vitamin K1 given
Following administration of actinomycin D or ethionine to vitamin K-deficient rats, treatment with vitamin K1 markedly stimulated prothrombin production, indicating that the site of action of vitamin K is beyond the level of transcription of DNA to prothrombin messenger RNA
We have investigated the possible involvement of vitamin K in general protein synthesis by studying the incorporation in &JO and in vitro of radioactive L-(1J4C)-leucine
Summary
Experiments Involving Treatment with ProteinSynthesis-blocking AgentsVitamin K Treatment Experiments-nn-Ethionine and puromycin dihydrochloride were Nutritional Biochemicals products.Warfarin was obtained from K and K Laboratories, Inc., NewYork, and vitamin K1 from General Biochemicals. The results of our experiments with control, vitamin K-deficient, and warfarin-treated rats, in which protein synthesis has been blocked by actinomycin D or by cycloheximide (Actidione), are shown in Table IV and Fig. 1 through 3. E$ect of actinemycin D and cycloheximide on incorporation in vivo of mixed 14C-amino acids (5 C/l00 g of body weight, injected 1 hour prior to sacrijice) into microsomal and plasma proteins of vitamin K normal rats. With these controls available, it was possible to study the response of vitamin K-deficient or warfarin-treated rats to vitamin Ki given simultaneously or at various time intervals following administration of the different protein synthesis-blocking agents. From the data on control rats given 2000 pg/lOO g of body weight of actinomycin D (Fig. 3b, Curve C-5), it appeared that prothrombin synthesis was continuing at a rate sufficient to keep blood prothrombin above 50% of normal for 6 hours, but that after 6 hours, a sharp break in the curve occurs presumably due to exhaustion of mRNA for prothrombin synthesis; and thereafter a rapid fall in blood prothrombin, similar to that seen after cycloheximide, occurs
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