HEyviIGLOBIN FORMATION BY FOREIGN SUBSTANCES 519 



of rabbit erythrocytes (8 ^1- oxygen per gram moist cells per hour) 

 and by assuming that the oxygen is activated via the autoxidation 

 of hemoglobin, one can calculate the rate of hemoglobin formation 

 to correspond roughly to 8% per hour. The fact that hemo- 

 globin during the physiological cycle of oxygen carriage spends an 

 appreciable fraction of its life at oxygen tensions close to those optimal 

 for hem/globin formation, might increase the rate of autoxidation 

 in vivo over that in vitro, so that the figure may well be a minimum 

 estimate. Cox and VVendel (508) found that high concentrations of 

 hem/globin in the erythrocyte of the dog were reduced at a rate 

 corresponding to 10-12% of the total pigment per hour. At lower 

 concentrations of henuglobin the rate of reduction is slower, and, if 

 we can compare this set of data, the reducing systems are adapted to 

 keep all but a small percentage of the total pigment functional. This 

 neglects the possibility of hemiglobin formation by oxidizing sub- 

 stances other than oxygen. An increased amount of hemiglobin in 

 the circulation would be expected to follow an increased rate of 

 formation or a diminished efficiency of reduction.* 



4.2. Hemiglobin Formation by Foreign Substances 



A great variety of substances have been shown to produce clinical 

 hemiglobinemia. These include the chlorate and nitrite ions and 

 various organic nitrites; among commonly used drugs phenacetin, 

 acetylsalicylic acid (357), and the sulfonamides {929,1142,1768,2264, 

 2265,2271,2577,3007,3036), and among the industrial poisons aro- 

 matic nitro and amino compounds are extremely active. The physi- 

 ology and toxicology of the latter class of substances have been 

 carefully reviewed by Von Oettingen (2067,2069) and by Heubner 

 (1254). 



In spite of the fact that the formation of hem?globin is a reversible 

 alteration, its detrimental effect has probably been underestimated. Recent 

 observations have shown that its effect on the oxygen-carrying capacity of 

 hemoglobin is greater than corresponds to the amount of hemoglobin trans- 

 formed into hemoglobin. This is caused by the influence of hem/globin on 

 the dissociation curve of oxyhemoglobin (532,1722a), cf. Chapter VI. Increase 



* Both factors are evidently of importance in familial hem?globinemia. Evidence 

 for lack of reducing systems has been found (King, White, and Gilchrist, lo-Ha; Gibson, 

 9'JSa). On the other hand, Fishberg {902a) shows that in this disease, as well as in 

 scurvy, tyrosine is incompletely metabolized with the formation of benzoquinone 

 acetic acid. This quinone oxidizes hemoglobin to hemiglobin; ascorbic acid diminishes 

 the heniiglobinemia by preventing the formation of the benzoquinone acetic acid. 



