512 5. QUINONES 



order: cat > dog > rabbit > rat > mouse > guinea pig. For some quinones 

 and routes the differences between the rodents are probably insignificant. 

 Monkeys and man are undoubtedly more susceptible than the above ani- 

 mals but there are too few reports to evaluate this quantitatively. There is 

 surprisingly little difference between the doses for benzo- and naphthoqui- 

 nones; the mean intravenous doses for both may be given as: toxic dose 

 10-15 mg/kg, LD50 25-30 mg/kg, and LD95 50-60 mg/kg. The relative 

 doses given by different routes are approximately: intravenous 1, subcuta- 

 neous 2, and oral 7.5. Such a large difference between intravenous and oral 

 doses is to be expected in the case of substances which are unstable or 

 easily metabolized or bound readily to the tissues. j)-Benzoquinone is usually 

 2-4 times more toxic than the hydroquinone, which is somewhat unexpected, 

 even if the quinone form is active, since one might predict that equilibrium 

 between the two forms would be fairly rapidly achieved in the body. The 

 difference is seen when they are given not only by the intraveous route, 

 but also by the subcutaneous and oral routes. That menadiol seems to be 

 more potent than menadione is even more unexpected, but Ansbacher et 

 al. (1942) felt this to be an artifact due to different solvents used, although 

 the chronic subcutaneous experiments of Shimkin (1941) showed a similar 

 relationship. Quite possibly of course the polyphenols exert some of the 

 effects directly and do not have to be transformed into quinones; indeed, 

 it is known that resorcinol, for example, elicits central effects similar to 

 those produced by 2>-benzohydroquinone (Seifter, 1948). It is certainly 

 true that menadiol-diP and other derivatives in which the hydroxy groups 

 are masked are much less active. It is impossible to estimate accurately 

 the blood concentrations produced by toxic doses, because the rates of 

 absorption and destruction, and the fractions bound, are unknown. Yet it 

 is quite obvious that blood levels around 1 mM could be achieved and that 

 levels near 3-5 niM must be reached following intravenous administration. 

 Thus the actions of the quinones on enzymes and metabolic systems at 

 these seemingly high concentrations cannot be considered as artificial in 

 relating them to the effects on the whole animal and attempting to ascertain 

 the mechanism of the toxic actions. The quinones are probably not cumula- 

 tive poisons generally when given daily in toxic or subtoxic doses in terms 

 of blood or tissue concentrations, although progressive enzyme inactivation 

 or tissue damage may occur. Sometimes near-toxic doses may be given 

 daily without marked effects and this is undoubtedly due to the rapid 

 metabolism of the quinones and hydroquinones in the body. 



Actions on the Central Nervous System 



There is good evidence that the signs of central stimulation derive from 

 a direct action and are not the result of asphyxia, methemoglobinemia, hy- 

 poglycemia, or peripheral actions. One of the earliest actions is to induce 



