EFFECTS IN THE WHOLE ANIMAL • 517 



is marked at least a temporary stimulation of the hematopoietic system 

 has been noted. The hemolytic action of the quinones has been mentioned 

 frequently (Oettel, 1936), but whether this is the result of a direct action 

 on the erythrocytes or to be attributed to some action on the liver has been 

 debated. In favor of the former hypothesis, quinones have been shown to 

 be hemolytic in vitro, and structural changes in the circulating erythrocytes 

 have been observed during menadione administration (Fromherz, 1941). 

 Menadione is hemolytic at concentrations between 0.00063 and 0.0063 mM. 

 However, 1,2- and 1,4-naphthoquinone are much less active on human blood, 

 hemolysis being produced only by concentrations above 1 mM (Rieders 

 and Brieger, 1951). No in vivo hemolysis was observed with these substances. 

 There is little if any direct evidence in favor of the liver hypothesis; although 

 liver damage has been reported following toxic doses of the quinones, there 

 is no reason to relate this to hemolysis, and indeed hemolysis and anemia 

 will occur at doses much lower than those giving rise to significant liver 

 changes. 



Inasmuch as vitamin K is a naphthoquinone required for the synthesis 

 of prothrombin in the liver, there is the possibility that certain naphtho- 

 quinone derivatives might depress prothrombin synthesis by competitive 

 interference and hence lead to a hemorrhagic state. Woolley (1945 a) 

 tested 2,3-dichloro-l,4-naphthoquinone in weanling mice on a vitamin 

 K-deficient diet and found that it reduces the survival time. However, the 

 animals do not bleed and the prothrombin is normal, and furthermore 

 neither vitamin K nor menadione protects. It appears that this derivative 

 is incapable of interfering with prothrombin synthesis. On the other hand, 

 2-chloro-l,4-napthoquinone and 3-hydroxy-2-chloro-l,4-napthoquinone are 

 weak antagonists of vitamin K and can produce a deficiency state character- 

 ized by prolongation of the clotting time (Meunier et at., 1945). It may be 

 mentioned that some of the antimalarial 2-hydroxy-3-alkyl-l,4-naphtho- 

 quinones produce a hemorrhagic syndrome without damaging the liver or 

 reacting with prothrombin directly, and the administration of vitamin Kj 

 is effective in preventing this (C. C. Smith et al., 1946). 



Factors Altering the Susceptibility to Quinones 



Vollmer and his colleagues at Breslau studied the effects of various fac- 

 tors on the toxicity of p-benzohydroquinone in order to determine if there 

 is a relationship to the metabolic rate of the animals. His basic concept 

 was that the toxicity of a hydroquinone is dependent on its oxidation to 

 the corresponding quinone, and that the more active the metabolism of the 

 animal, the more readily would this occur and the greater the toxicity. 

 Administration of thyroxine to mice until they are hyperthyroid increases 

 the susceptibility to p-benzohydroquinone; at a dose of 150 mg/kg sub- 

 cutaneously, the normal mice mainly recover whereas the hyperthyroid 



