/ /» XII. VITAMINS K 



for oral administration.-^^ When toxicity develops, death usually results 

 from circulatory ^^^ or respiratory failure.'-^' In mice, also, respiratory 

 failure is the cause of death. -■^^ 



When menadione was given in a high dosage (0.3% of the diet), growth 

 was found to be depressed;-^- when the proportion in the diet was further 

 increased to 0.8%, the inhibition of growth was more severe. Anemia 

 and splenomegaly also occurred. Anemia has been reported by a number of 

 workers as a symptom of overdosage of menadione in several species, in- 

 cluding the dog,^^^ the rat,-^^ and the rabbit. -^^ Polycythemia has been 

 observed in some cases in the same species. -^'^ Other symptoms of de- 

 ranged hemoglobin metabolism resulting from excessive doses of mena- 

 dione include methemoglobhiemia,-^^ porphyrhmria, albuminuria'-"'^'*^ 

 and hemorrhagic extravasations into the liver and kidneys. 2*^ Methemo- 

 globin formation has been found to occur in vitro r"^^ Phytyl menadione 

 (vitamin Ki) does not cause a similar toxicity.'-" 



9. Comparative Activity of Vitamin K-Active Compounds 



The molecular structure reciuired for maximum activity is that present 

 in 2-methyi-l,4-naphthoquinone. This compound has been given the 

 non-proprietary name of menadione, by the American Medical Associa- 

 tion.-*^ Thaj^er et al.~^^ adA'ised the employment of this compound as a 

 standard of activity, 1 jug. being defined as one unit. Ewing et air*'' 

 suggested that 2-methyl-l,4-naphthohydroquinone diacetate might be 

 preferable as a standard, in spite of the fact that it possesses only one-half 

 of the biopotency of menadione. Vitamin Ki is only 50% as active as 

 menadione; it contains the heavy long aliphatic hydrocarbon side chain 

 which contributes nothing to its biopotency. Since the difarnesyl side 

 chain on vitamin K2 is longer and heavier than the phytyl side chain on 

 vitamin Ki, the biopotency of vitamin K2 is appreciably less than that of 

 vitamin Kj. For a more complete exposition of the vitamin K biopotencj^ 

 of related compounds, the reader is referred to the paper of Fieser, Tishler, 

 and Sampson, 2^ and to The Lipids, Volume I, pp. 844-859. 



"1 R. H. K. Foster, Proc. Soc. Exptl. Biol. Med., 45, 412-415 (1940). 



242 E. H. Hatton, A. Dodds, H. C. Hodge, and L. S. Fosdick, /. Denial Research, U, 

 283-295(1945). 



2" F. Ivoller, Schiveiz. med. Wochschr., 69, 1159-1161 (1939). 



2« A. Cannavd, Bull. soc. ital. biol. sper., 2A, 593-594 (1948). 



24* Anonj^mous, Coimcil on Pharmacy and Chemistry, J . Am. Med. Assoc, 116, 1054 

 (1941). 



2« S. A. Thaver, S. B. Binklev, D. W. MacCorquodale, E. A. Doisy, A. D. Emmett, R. 

 A. Brown, and O. D. Bird, J. Am. Chem. Soc, 61, 2563 (1939). 



2" D. T. Ewing, J. M. Vandenbelt, and O. Kamm, /. Biol. Chem., 131, 345-356 (1939). 



