444 VITAMIN K GROUP 



in vitro. Other toxic manifestations in animals are prophyrinuria, albumin- 

 uria,^^ and hemorrhagic extravasations into the liver and kidneys. ^^ 



It may be noted that the naturally occurring phytyl menadione is non- 

 toxic in amounts that would be lethal if comparable quantities of the 

 artificial vitamins had been given. Similarly, when the solubilizing ester 

 chains are lengthened, toxicity decreases (Table VI). As the toxicity de- 

 creases with increasing molecular size, so does the antihemorrhagic activity; 

 the two functions seem not to be directly related, however, for the former 

 diminishes at a much greater rate than the latter. An even more striking 

 example of disparity between activity and toxicity is the effect of methyla- 

 tion of naphthoquinone: toxicity diminishes 75%, prothrombinogenic 

 activity increases 2000-fold.^^ 



Potentially, one of the more serious toxic manifestations of vitamin K 

 would be overcorrection of the prothrombin deficiency, that is, "hyperpro- 

 thrombinemia." This has actually been reported^""- ^°^ and also denied. ^"^^ ^°* 

 Curiously, the excess prothrombin is detected by one method alone: "pro- 

 thrombin times" on diluted (1:8) plasma. It should be noted that with this 

 method the fibrinogen concentration of the tested plasma is suboptimal 

 and the test may reflect fibrinogen changes^"'' as readily as it does other 

 clotting factors; elevation of plasma fibrinogen has been noted with large 

 doses of vitamin K.^"* 



IX. Requirements 



A. OF ANIMALS 



H. J. ALMQUIST 



1. Chick 



Factors influencing the incidence of dietary hemorrhagic disease in chicks 

 were discussed by Almquist and Stokstad.^ It was found that the vitamin 

 was synthesized in the droppings of chicks and in the lower intestinal tract 

 where appreciable absorption did not take place. The vitamin K intake of 



loo R. S. Overman, J. B. Field, C. A. Baumann, and K. P. Link, J. Nutrition 23, 589 



(1942). 

 '0' J. B. Field and K. P. Link, J. Biol. Chem. 156, 739 (1944); P. N. Unger and S. 



Shapiro, Blood 3, 137 (1948). 

 i»2 A. J. Quick, J. Lab. Clin. Med. 31, 79 (1946). 



103 C. E. Brambel and F. F. Loker, Proc. Soc. Exptl. Biol. Med. 53, 218 (1943). 

 10" H. F. Deutsch and H. W. Gerarde, J. Biol. Chem. 166, 381 (1946). 

 105 G. A. Nitsche, Jr., H. W. Gerarde, and H. F. Deutsch, ./. Lab. Clin. Med. 32, Part 



1, 410 (1947). 

 1 H. J. Almquist and E. L. R. Stokstad, /. Nutrition 12, 329 (1936). 



