522 XI. HEMOGLOBIN CATABOLISM, I 



4.3. Reduction of Hemiglobin in Vivo 



In addition to the work on the mechanism of hem?'globin reduction in 

 erythrocytes discussed in Section 3.2., there exist a number of investigations 

 into the reduction in vivo {986,1108,125Jf,1260-1262,lJtS8,1526,2173,2U5). 

 One of the best is that of Cox and Wendel {508) who found a rate of reduction 

 of hemiglobin formed by intravenous injection of nitrite in dogs, correspond- 

 ing to 11 to 12% of total hemoglobin per hour. 



This was independent of total hemoglobin and of hemiglobin concentration 

 (as long as hemrglobin formed more than 20% of the blood pigment), and 

 independent of the way in which hemrglobin had been formed (unless sub- 

 stances were used which are only gradually transformed into active catalysts). 

 In contrast to Brooks {SJ^Ji) no influence of the glucose content of blood on 

 the rate of reduction was found. The rate was decreased by low body tem- 

 perature. Methylene blue increased the rate of reduction (cf. also 1178,1526), 

 but successive doses were less and less effective. Methylene blue has found 

 clinical application in the abolition of hem?globinemia caused by sulfonamides 

 {398,11^2). The differences in sensitivity of various animal species to hemi- 

 globin-forming drugs depend largely on the efficiency of the reducing systems 

 {986,125J^,1260,U38,1530,1722). 



It is uncertain what role substances such as ascorbic acid and glutathione 

 {cf. Sections 3.3. and 3.3.2.) plaj' in the normal reduction of hemoglobin. 

 The fact that ingestion of ascorbic acid has been shown to bring about a 

 significant reduction in the hemzglobin level in idiopathic familial hemi- 

 globinemia (551,104.0,1728) speaks in favor of the assumption that this 

 compound might also be involved under normal conditions, but the point 

 is far from settled (cf. the footnote on p. 519). 



Glutathione reduces hemoglobin (1991) as does cysteine (64-1, 1526, 1991). 

 Cox and Wendel (508) found, however, no diminution of the rate of hemi- 

 globin reduction after repeated doses of nitrite in vivo, which were sufficient 

 to oxidize the total blood hemoglobin to hemiglobin four times. To judge 

 from the work of Keilin and Hartree (1498), quoted in Section 3.3.1., all 

 glutathione should have been oxidized by this procedure. 



The inhibition of reduction of hemiglobin by drugs and poisons possibly 

 contributes to their effect of causing hemiglobinemia. Nitrophenols inhibit 

 cytochrome reductase (1076,1575; cf. also Kensler and co-workers, 1519). 



5. INTRACORPUSCULAR ALTERATIONS PRECEDING 



DESTRUCTION OF THE ERYTHROCYTE 



AND HEMOLYSIS 



5.1. Introduction 



The existence in the erythrocyte of an oxidation-reduction cycle 

 with intracellular hemoglobin formation and reduction, even if slow, 

 may be assumed ultimately to bring about the destruction of the 

 reducing enzyme systems. Since most of these are also concerned 



