504 XI. HEMOGLOBIN CATABOLISM, I 



with bile fistula animals, demonstrated that the introduction of pure 

 hemoglobin into the circulation led to increased excretion of bile 

 pigment by the liver, that the ability of the animal body to convert 

 hemoglobin into bilirubin became generally accepted. The latter has 

 been confirmed by a number of workers (371,372,998,2605), and 

 Whipple and his collaborators (cf. Section 8.1.) later showed that the 

 prosthetic group of hemoglobin is almost quantitatively converted 

 into bilirubin. 



Bilirubin is excreted by the liver into the bile and thus reaches the 

 intestine, in which it is transformed into urobilinogen and urobilin 

 (cf. Chapter IV). Jaffe {U07), who, in 1868, first discovered urobilin 

 in urine, considered that it was related to the bile pigments. In view 

 of the fact that bilirubin is present in much greater concentration in 

 the bile than at the end of the alimentary canal, where only traces 

 exist, urobilin was always considered to be a further breakdown prod- 

 uct of bilirubin. Miiller (1994) confirmed this by demonstrating the 

 presence of urobilin in the urine after feeding bile to a patient with 

 an occluded bile duct. A part of the intestinal urobilin is reabsorbed 

 from the intestine and excreted again by the liver (enterohepatic 

 circulation). Normally only small amounts of urobilin and only 

 traces of bilirubin appear in the urine. 



1.2. Earlier Theories of the Mechanism 



With the recognition that the transformation of hemoglobin to 

 bile pigment involved the removal of iron and protein, and the pro- 

 found alteration of the structure of the prosthetic group, theories 

 were formulated as to the possible steps. Almost all hypotheses 

 ignored obvious physiological and histological hints as to the chain of 

 reactions, and envisaged the transformation almost solely in terms 

 of chemical steps which could be carried out at that time in the test 

 tube. As a result of the isolation of hematin and hematoporphyrin 

 the steps were considered to be hemoglobin, hematin, hemato- 

 jlorphyrin, bilirubin (371,372,697,1859). While Brugsch's school 

 (370-372) claimed that they had observed increases in bilirubin 

 excretion after injection of hematin, and in this received some sup- 

 port from Van de Velde (286Jf) ,* these findings have not been con- 

 firmed by Gitter and Heilmeyer (1007) or by Duesberg (639). Intra- 

 venous injection of hemoglobin is followed by large increases in 

 serum bilirubin and rapid excretion of bilirubin in the bile, but the 



*And more recently by Benard and co-workers {211). 



