THE REGULATORY FUNCTION OF THE FAT-SOLUBLE VITAMINS

The regulation of cell metabolism involves controls imposed at three general levels: (a) modification of the activity of existing enzymes, (b) modification of the permeability and function of cell and organelle membranes, and (c) the control of the synthesis of enzymes and other proteins of biological significance mediated by genetic mechanisms. Attempts to explain the action of the fat-soluble vitamins in terms of the first two mechanisms cited above have not been successful. In view of the fact, however, that the fat-soluble vitamins, as a class, do influence the concentrations of enzymes and other proteins in various organisms, it appeared possible that these changes reflected an action at the genetic level.It has been shown that actinomycin D inhibits vitamin K induced prothrombin formation in chicks deficient in vitamin K. Doses of actinomycin which inhibited the normal response to vitamin K inhibited incorporation of adenine-8-C14into hepatic RNA. These results were consistent with the hypothesis that vitamin K acts by stimulating messenger RNA formation for the synthesis of clotting proteins. Since the coumarin drugs antagonize vitamin K, it seemed possible that the site of antagonism was a molecule which regulates this expression of genetic information. To test this hypothesis, rats were fed a diet containing 0.05% dicumarol for 48 hours, at which time they showed prolonged clotting and one-stage prothrombin times. This clotting defect could be corrected in 6 hours by the administration of 1 mg of vitamin K1to each rat by mouth. The administration of actinomycin D in closes from 30 to 240 μg per 100 g body weight 4 hours before vitamin K1either modified or prevented the action of the vitamin. If actinomycin was given after the vitamin, or given to normal rats, no anticoagulant effect was noted. These data are consistent with the view that the site of antagonism between vitamin K and the coumarin drugs is a molecule which controls DNA-dependent RNA replication.