520 XI. HEMOGLOBIN CATABOLISM, I 



in the rate of hemiglobin formation may be due to direct oxidation of oxy- 

 hemoglobin, to the formation of hemiglobin by coupled oxidation, and to the 

 formation of hydrogen peroxide within the cell in such a way that it can act 

 on hemoglobin in spite of the presence of catalase. 



Nitrite and chlorate undoubtedly oxidize hemoglobin to hemiglobin 

 without affecting the rate of reduction of hemoglobin (Section 4.3.)- 



The mechanism is more complicated in the case of the aromatic nitro 

 and amino compounds; they are primarily converted either into phenyl- 

 hydroxylamines or into aminophenols, both of which readily form hemo- 

 globin from oxyhemoglobin (cf. Heubner, 125If,1255; Von Oettingen, 2067; 

 Wendel and Cox, 508). EUinger {661) and Lipschitz {1761) obtained evi- 

 dence to show that aromatic amino as well as nitro compounds are converted 

 first into phenylhydroxylamines. Heubner and his school, however, attrib- 

 uted the hemoglobin formation by aromatic amines to the formation of 

 aminophenols, particularly p-aminophenol {246,1259,1261,2517). Both 

 hydroxylamino compounds and aminophenols can be formed by reduction of 

 aromatic nitro compounds, e.g., trinitrotoluene (Lemberg and Callaghan, 

 1693) in vivo, and may contribute to hem/globin formation. 



The formation of hemOglobin by these compounds is a true catalysis, eight 

 equivalents of hem/globin being formed, for example, per mole of p-amino- 

 phenol. To explain the catalytic effect of p-aminophenol Heubner assumed 

 that the product of its autoxidation, p-iminoquinone, is the actual oxidizer 

 of hemoglobin. Alcohol, which is- known to enhance the toxicity of aromatic 

 nitro compounds {cf. 2517), delays the removal of the iminoquinone system, 

 while it does not interfere with the reduction of hemoglobin {cf. 1254). 

 Against the correctness of the hypothesis of Heubner doubts have been raised 

 by Williams {3085) ; the glucuronides of aminophenols which cannot readily 

 yield iminoquinones were also found to be active hemOglobin formers. 



Heubner {1254,1255) discusses as an alternative explanation the formation 

 of hydrogen peroxide by autoxidation (or reaction with oxyhemoglobin) of 

 the hydrogen donor and oxidation of hemoglobin to hemOglobin by the hydro- 

 gen peroxide thus formed. This hypothesis can be applied for phenyl- 

 hydroxylamine as well as for aminophenols. With regard to the latter, the 

 hypothesis is actually not alternative, but complementary to the first, since 

 both the hydrogen peroxide and the iminoquinone are able to oxidize hemo- 

 globin. Phenylhydroxylamine and also hydroquinone {1254) are more rapidly 

 oxidized by oxyhemoglobin than by atmospheric oxygen; the primary reac- 

 tion in these instances must be assumed to be: 



HbOa -f HoA -^ Hb • H2O2 + A 



rather than: H2A +02"^ H2O2 + A 



The secondary reaction depends on the nature of A ; if it is a quinone, it will 

 oxidize hemoglobin to hemOglobin, while nitrosobenzene formed from phenyl- 

 hydroxylamine unites with hemoglobin. Finally, hemOglobin may be reduced 

 back to hemoglobin by the hydrogen donor and, after recombination of 

 hemoglobin with oxygen, the cycle begins once more; in this case irreversible 

 oxidation of hemoglobin to choleglobin is the final result {cf. Chapter X, 



