418 VITAMIN K GROUP 



prothrombin deficiency. This could be prevented by adding vitamin K to 

 the diet. Confirming observations have been reported.^^- "® 



C. NATURAL ANTAGONISTS 



A hemorrhagic agent isolated from spoiled sweet clover hay has been 

 shown to be a dicoumarin by Link and coworkers.-'^ The compound isolated 

 is 3,3'-methylenebis(4-hydroxycoumarin). When given to various species 

 of animals this compound induces a decrease in prothrombin which is most 

 profound when associated with low vitamin K intake and can be reversed 

 by vitamin K administration.^^ - -^ The dicoumarin is easily degraded to 

 salicylic acid by chemical means, and this fact suggested that the acid 

 might be produced by the metabolism of the dicoumarin. Administration of 

 salicylic acid to rats, either in the vitamin K-low diet or intravenously, 

 caused a hypoprothrombinemia similar to that produced by the dicoumarin 

 or by vitamin K deficiency. The effect was reversed by vitamin K. Neither 

 the dicoumarin nor salicylic acid had any effect on the clotting power of 

 blood in vitro (Link et alP). This subject is more fully discussed in Section 

 VII B of this chapter (p. 432). 



Woolley^" observed that a-tocopherolquinone administered to pregnant 

 mice caused hemorrhagic symptoms in the reproductive system and resorp- 

 tion. The action of the a-tocopherolquinone was not prevented by large 

 doses of vitamin E but was reversed by small doses of vitamin K. The struc- 

 tural similarity of a-tocopherolquinone and vitamin Ki was pointed out as 

 an explanation of the antivitamin activity. 



Excessive intake of vitamin A is known to cause a variety of toxic effects 

 among which is a hemorrhagic tendency and prolonged coagulation time of 

 blood. The clotting defect as produced in rats may be remedied by a gener- 

 ous intake of vitamin K.^^ The condition has been produced by alcohol and 

 ester forms of vitamin A prepared from natural sources, but it has not yet 

 been reported as caused by synthetic vitamin A. It remains to be seen if 

 vitamin A itself or some associated substance is the cause of these hemor- 

 rhagic tendencies. In chicks, even large doses of vitamin A had no effect on 

 the prothrombin time although the chicks received only a minimal level of 

 vitamin K. The effects in rats, therefore, may have been due to interference 

 in the synthesis of vitamin K by intestinal microorganisms.^^ 



25 A. D. Welch and L. D. Wright, /. Nutrition 25, 555 (1943). 



26 H. G. Day, K. G. Wakim, M. M. Krider, and E. E. O'Banion, J. Nutrition 28, 

 585 (1943). 



" H. A. Campbell and K. P. Link, /. Biol. Chem. 138, 21 (1941). 



28 A. J. Quick and M. Stefanini, J. Biol. Chem. 175, 945 (1948). 



29 K. P. Link, R. S. Overman, W. R. Sullivan, C. F. Huebner, and L. D. Scheel, 

 J. Biol. Chem. 147, 463 (1943). 



30 D. W. Woolley, J. Biol. Chem. 159, 59 (1945). 



31 R. F. Light, R. P. Alscher, and C. N. Frey, Science 100, 225 (1944). 



