AMINOPHENOLS AND PHENYLENEDIAMINES 593 



When p-phenylenediamine is added to melanoma extracts there is a rapid 

 increase in the oxygen uptake, and this is unique because the extra respira- 

 tion is not inhibited by cyanide (Riley, 1958). It was found that this arises 

 from a nonenzymic reaction between ^^-phenylenediamine and dopa. Mice 

 bearing melanomas are less susceptible than normal mice to the toxic ef- 

 fects of p-phenylenediamine, while they are more susceptible to o-phenyl- 

 enediamine. These relationships led to the testing of the diamines for car- 

 cinostatic activity (Riley, 1959). o-Phenylenediamine was found to be more 

 effective and less toxic than p-phenylenediamine, and could suppress the 

 in vivo growth of mouse and hamster melanomas and Ehrlich solid car- 

 cinomas. Complete inhibition of the latter tumor could be achieved and 

 occasionally complete remission of established tumors. It is not known if 

 the reaction with catecholamines is involved in the growth inhibition. 

 The phenylenediamines were found to inhibit the respiration of Ehrlich 

 ascites cells but to have little or no effect on the glycolysis, and it was con- 

 cluded that the NAD-linked enzymes are not the sites of attack, as had 

 been suggested by Kensler et al. (1942 b). However, since the data and 

 conditions were not presented, it is impossible to judge the validity of 

 this conclusion. 



Effects on Tissues and in Whole Animals 



The pharmacology of the phenylenediamines and their methyl and di- 

 methyl derivatives was well studied by Hanzlik (1923 a, b). The toxic 

 and fatal doses seem to be of the same magnitude as for p-benzohydroqui- 

 none (see Table 5-5), namely, around 100-200 mg/kg subcutaneously, 

 although the methylated derivatives are somewhat more toxic. The effects 

 on the heart and circulation are complex and presumably related to direct 

 actions on the vessels and myocardium since they are independent of in- 

 nervation. The heart is not very sensitive to the phenylenediamines and 

 stops in diastole at high concentrations or doses. No mention was made of 

 contracture in either the heart or skeletal muscles. There is surprisingly 

 little difference in the effects of the para and meta isomers, which may in- 

 dicate that the quinonoid form is not involved in the toxicity. Tainter and 

 James (1929) found that o-phenylenediamine is not only weaker phar- 

 macologically than the 'para isomer, but produces a different pattern of 

 effects. It is difficult in any of this work to compare the phenylenediamines 

 with the quinones because they were never examined under comparable 

 conditions. 



The phenylenediamines are irritants and vesicants (Hanzlik, 1923 a); 

 they share this action with p-benzoquinone and other penetrable SH 

 reagents, but whether this is due to inhibition of pyruvate oxidation is 

 not known. p-Phenylenediamine and p-benzoquinone act very similarly 

 on the conjunctiva, producing inflammation and edema (Estable, 1948). 



