VII. EFFECTS OF DEFICIENCY 429 



and Quick^^ depleted dogs of vitamin K stores by cholecystnephrostomy; 

 small doses of vitamin Ki (or analogs) and of dicoumarol counteracted 

 each other. Because of the minuteness of the doses, Collentine and Quick 

 feel that the only explanation is a mutual competition for prothrombino- 

 genic enzyme systems. Almquist^"" has presented an interesting theoretical 

 analysis of the action of dicoumarol. 



Certain observations suggest a primary hepatotoxicity from dicoumaroli- 

 zation. Overdoses of dicoumarol produce fatty livers in rabbits*^ and central 

 necrosis of the liver in rats.^^ Bollman and Preston^'' reported that in the 

 presence of an already damaged liver the effect of dicoumarol was accen- 

 tuated. Similarly, Roller and Mudrak^^ demonstrated that, if the liver had 

 been damaged, smaller doses of dicoumarol gave the same effect as large 

 doses when hepatic function was normal. Irish and Jaques^- noted that 

 dicoumarol, like known hepatotoxins, stimulated fibrinogen production if 

 given in small doses, and in larger doses depressed the fibrinogen of the 

 blood. 



The concept of a competition between vitamin K and dicoumarol has 

 been explored extensively by Meunier and Mentzer;^^ these investigators 

 have stressed the similarity between compounds with hemorrhagic and 

 antihemorrhagic activity. Menadione (Fig. 5) (1) is a potent vitamin K 

 analog; addition of an hydroxyl in the 3 position, phthiocol (2), reduces 

 the activity; replacement of the methyl by an ethyl radical (3) further 

 weakens the antihemorrhagic power; combining two phthiocols through 

 their methyl groups yields an antivitamin K^* (4), as does doubling menadi- 

 one^" (5). Replacing the 2-methyl group in menadione by methoxy (6) also 

 reverses the compound's action, ^^ and if one substitutes for the methyl in 

 phthiocol's 2 position 3-cyclohexylpropyl (7), or 2-methyloctyl (8), or 

 3-(decahydro-2-naphthyl)propyl (9) radicals, a similar reversal occurs.^'' 

 Some of the more potent hemorrhagic agents tend to resemble (4) and (5), 

 that is, "double molecules." Although most clinical anticoagulants are 



^'^^ H. J. Almquist, Arch. Biochem. and Biophys. 35, 463 (1952). 



88 K. F. Jansen, Nord. med. 20, 1993 (1943). 



89 C. L. Rose, P. N. Harris, and K. K. Chen, Prnc. Soc. Exptl. Biol. Med. 50, 228 

 (1942). 



9" J. L. Bollman and F. W. Preston, J. Am. Med. Assoc. 120, 1021 (1942). 



91 D. Roller and O. Mudrak, Z. ges. exptl. Med. 114, 75 (1944). 



92 U. D. Irish and L. B. Jaques, Am. J. Physiol. 143, 101 (1945). 



9^ Reviewed in several articles in the International Colloquy "Les Vitamins," Bull. 



soc. chim. hiol. (1948). 

 9^ P. Meunier, C. Mentzer, N.P. Buu-Hoi, and P. Cagniant, Bull. soc. chim. hiol. 25, 



384 (1943). 



95 C. Mentzer, Bull. soc. chim. biol. 30, 872 (1948). 



96 D. Molho, J. Moraux, and P. Meunier, Bull. soc. chim. biol. 30, 637 (1948). 



97 C. C. Smith, R. Fradkin, and M. D. Lackey, Proc. Soc. Exptl. Biol. Med. 61, 398 

 (1946). 



