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Studies on the mode of action of vitamin K

1966; Pergamon Press; Volume: 4; Linguagem: Inglês

10.1016/0065-2571(66)90014-8

1873-2437

Robert E. Olson,

Vitamin K Research Studies

The regulation of cell metabolism involves controls imposed at three general levels: (1) modification of the activity of existing enzymes, (2) modification of the permeability and function of cell and organelle membranes, and (3) 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-8-14C into hepatic RNA. These results were consistent with the hypothesis that vitamin K acts by stimulating messenger RNA formation for the synthesis of clotting proteins. Puromycin was also shown to inhibit the response to vitamin K in proportion to its inhibitory effect on liver protein synthesis. 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 per cent dicumarol for 48 hr, at which time they showed prolonged clotting and one-stage prothrombin times. This clotting defect could be corrected in 6 hr by the administration of 1 mg of vitamin K1 to each rat by mouth. The administration of actinomycinD in doses from 30–240 μg/100 g body weight 4 hr prior to the vitamin K1 either 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. The dose-response curve of vitamin K-deficient chicks to vitamin K3 in the presence and absence of prior dicumarol was suggestive of an allosteric interaction. 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.