MODERN VIEWS OF HEMOGLOBIN BREAKDOWN 507 



regularly accompanies bilirubin in the serum of patients with car- 

 cinomatous obstruction of the common bile duct, and frequently in 

 that of patients with liver cirrhosis, catarrhal jaundice, and bile duct 

 occlusion by gall stones (1650,2199,2990). 



Some of the hitherto unexplained facts in bile pigment physiology 

 are probably due to the neglect to search for biliverdin when no bili- 

 rubin could be found. As far back as 1882, Neumann observed that 

 hemosiderin formation preceded the appearance of hematoidin crystals. 

 This has recently been confirmed by Muir and Niven {2002). Since 

 the organic moiety of the prosthetic group must become free when 

 iron is split off, the most likely explanation is that diffuse biliverdin 

 has escaped notice at the stage' when iron is removed and deposited 

 as hemosiderin. 



1.4. Modern Views on the Mechanism 

 of Hemoglobin Breakdown 



The demonstration of the conversion of hematin compounds to 

 bile pigments (Chapter X), without either free hematin or free por- 

 phyrin occurring as intermediates, provides the basis for an hypoth- 

 esis of hemoglobin breakdown which entirely supersedes the earlier 

 hypothesis discussed in Section 1.2. The mechanism of the reaction 

 involves the oxidative rupture of the porphyrin ring of hemoglobin 

 before separation of the prosthetic group from iron and globin. The 

 fact that biliverdin is the bile pigment most closely allied to the 

 choleglobin or verdoheme compounds, which occur as intermediates, 

 provides the key to the correct assessment of the numerous observa- 

 tions which have just been discussed as to the occurrence of biliverdin. 



The new hypothesis is based on experiments in which substances 

 found in vivo are allowed to react with hemoglobin under physio- 

 logical conditions of temperature, concentration, and pH to give 

 products which are also found in vivo. Its extension, however, to the 

 problem of hemoglobin metabolism in vivo requires the elaboration 

 of the basic mechanisms of the reaction at biochemical and physio- 

 logical levels of cell organization. The conversion of the prosthetic 

 group of hemoglobin into bile pigment appears to be quantitative in 

 vivo, while in vitro so far only a 15% conversion has been achieved. 



In their simplest form, the conditions required for the oxidative 

 disruption of the hematin ring — the presence of oxygen and of an 

 appropriate reducing system — are so generally present in living 

 cells that one would expect bile pigment formation to occur wherever 



