HEMIGLOBIN FORMATION BY FOREIGN SUBSTANCES 521 



Section 4.4.1.)- In this connection it is of interest that Seide {2528) found 

 phenylhydroxylamine to produce a 50% inhibition of catalase at 5 X 10"^ M, 

 and ;>-aminophenol, at 4 X 10"^ 3/ concentration. 



The mechanism of hemiglobin formation by the sulfonamides must 

 remain open.* On the basis of the theory that the antibacterial effects were to 

 be explained by an anticatalase action due to the formation of hydroxyl- 

 amine derivatives, hem?globin formation was thought to be due to a 

 mechanism analogous to that proposed by Ellinger and Lipschitz for other 

 aromatic amino compounds. There is little evidence, however, that such 

 derivatives are formed in vivo (2800) and it is more likely that hydroxysul- 

 fonamides are involved. On the other hand, Clyman {458) observed an 

 inhibition of the erythrocyte catalase in vivo, so the possibility that the 

 hem/globin is formed by hydrogen peroxide under conditions under which 

 the catalase is inhibited cannot be excluded ; Seide {2528) found sulfanilamide 

 to inhibit catalase only at rather high concentrations. Finally, the existence 

 of an inhibitory effect on the cell dehydrogenases and on the activity of 

 hydrogen carriers cannot be excluded. 



The strong increase in the respiration of the mammalian erythrocyte in 

 the presence of methylene blue was originally explained by Warburg and 

 Christian {29^1,294^2) as due to the oxidation of hemoglobin to hem/globin 

 and to the catalytic action of the latter compound on the oxidation of glucose 

 {cf. Section 3.2.). While methylene blue can be shown to form hemoglobin 

 cyanide in the presence of cyanide {1728), and thus like nitrite or p-amino- 

 acetophenone {2840) can be used to bind cyanide in the blood — thereby 

 protecting the respiratory ferment {ef. also 1254,1965,3034) — the methylene 

 blue catalysis of erythrocyte respiration is independent of hem?globin forma- 

 tion. Wendel {3033) has shown that hemoglobin cyanide does not oxidize 

 lactic acid in the erythrocyte, while the oxidation of lactate to pyruvate by 

 oxygen and methylene blue in the presence of the appropriate dehydro- 

 genases is not inhibited by cyanide. This view was later accepted by War- 

 burg and Christian {2932). ^l 



The increase of erythrocyte respiration by pheophorbid hemins observed 

 by Warburg and Kubowitz {2940) has been explained by these authors as 

 due to hem/globin formation. In view of the fact that their oxidation- 

 reduction potential is far lower than that of the hemoglobin-hemiglobin 

 system, the explanation appears unlikely. 



Hem/globin formation is also accelerated by pyridine {2251,2253), by a 

 substance present in the urochrome fraction in urine {2252) and a quinoid 

 substance present in pathological urine {902), naphthoquinones {1566,2525), 

 the D-amino acid oxidase system of kidney {245,247), and substances present 

 in liver extracts {567,641)- Since most of the experiments on these sub- 

 stances were carried out on hemolyzates, it is doubtful whether they have 

 any physiologic significance. + 



* According to Kallner {1/4.080) the cyanosis is due to the formation of a compound 

 of carbhemoglobin with sulfanilamide, rarely to hemoglobin. 

 t (/. also Kiese {1530b). 

 J With reference to quinones, see, however, Fishberg {903a). 



