Vitamin E in the reduced, a-tocopherol form shows very modest anticlotting activity. By contrast, vitamin E quinone is a potent anticoagulant. This observation may have significance for field trials in which vitamin E is observed to exhibit beneficial effects on ischemic heart disease and stroke. Vitamin E quinone is a potent inhibitor of the vitamin K-dependent carboxylase that controls blood clotting. A newly discovered mechanism for the inhibition requires attachment of the active site thiol groups of the carboxylase to one or more methyl groups on vitamin E quinone. The results from a series of model reactions support this interpretation of the anticlotting activity associated with vitamin E.With the success of recent field trials of vitamin E, and the attendant promise of forestalling the onset of heart attack and stroke (1, 2), it becomes important to understand the molecular mechanistic basis of this beneficent physiological activity. Since vitamin E is an excellent antioxidant (3-7) and radical inhibitor (8-11), these properties have been used, in general fashion, to interpret its physiological activity and its possible role in living systems (3)(4)(5)(6)(7)(8)(9)(10)(11)(12).It is known that vitamin E has anticoagulant properties (13-18), but this attribute has not been applied to understanding its physiological action. The recent Finnish study of male heavy smokers (19) found little efficacy of vitamin E and 13-carotene in preventing the occurrence of cancer, but the study did show the positive potential of vitamin E in cardiovascular therapy. There were clear benefits among the participants for ischemic heart disease and ischemic stroke, but, significantly, vitamin E acted to the detriment of those prone to hemorrhagic stroke (19). Accordingly, we suggest that the anticoagulant properties of vitamin E be included when evaluating the results of such trials.What are the anticoagulant properties of vitamin E, and why have they not been used in interpreting its physiologic role? For one, there has been some confusion about which oxidation states of vitamin E are effective anticoagulants, or, alternatively, which derivatives of vitamin E interdict the vitamin K-dependent clotting cycle and how effectively (20)(21)(22)(23). In response to the second part of the question, no mechanistic underpinning for the anticlotting properties of vitamin E has been developed, nor has there been any speculation regarding molecular mechanisms by which vitamin E might act as an inhibitor of the vitamin K-dependent carboxylase that is required to activate the enzymes of the blood clotting cascade. This paper will address both issues. ResultsThe vitamin K-dependent carboxylase and the other enzymes of the vitamin K cycle were obtained from rat liver microsomes (24,25). The uptake of 14C02 by the synthetic pentapeptide substrate FLEEI, as a function of inhibitor concentration, was used as a measure of carboxylase activity and its inhibition. The Vitamin E quinone 2 production of vitamin K oxide was conveniently monitor...
Congeners of vitamin K are known to inhibit cell growth, although the precise mechanisms of growth inhibition are not well understood. To investigate the mechanisms involved, we synthesized several vitamin K analogs and examined their growth inhibitory activities for a human hepatoma cell line (Hep3B). The analogs included 2-methyl-1,4-naphthoquinone and trimethyl-benzoquinone, with and without aliphatic side chains at position 3. The side chains were all-carbon, thioethers, or O-ethers. Growth inhibition was potent in the compounds with short chains. The presence of a sulfur (thioether) or oxygen atom (O-ether) at the site of attachment of the side chain to the ring potentiated the activity. Apoptotic cell death was induced by the potent growth inhibitory compounds at low concentrations (20-60 microM), whereas necrotic cell death followed treatment with the same compounds at high concentrations. Expression of c-myc, which is thought to be associated with apoptosis, was increased by most of the compounds tested. Both reduced glutathione and cysteine almost completely abrogated the growth inhibitory effects of the thioether analogs as well as of vitamin K3. The effect of glutathione was less prominent for the all-carbon and O-ether analogs, and cysteine had no effect on these analogs. Catalase and deferoxamine mesylate had no significant effect on the thioether analogs, although they showed partial antagonistic effects on the growth inhibition of vitamin K3 and the all-carbon and O-ether analogs. Other non-thiol antioxidants tested had no effect on any of the analogs. Our results indicated that vitamin K-related quinoid compounds cause growth inhibition and both apoptotic and necrotic cell death and that the effects may be mediated by interaction at position 3 of their quinoid nuclei with cellular thiols.
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