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Recent Studies Ofthe Urobilin Problem1 J Clin Pathol: first published as 10.1136/jcp.16.1.1 on 1 January 1963. Downloaded from J. clin. Path. (1963), 16, 1 --Recent studies of the urobilin problem1 C. J. WATSON2 From the Department of Medicine, University of Minnesota Hospital, Minneapolis, Minn. It is now almost a century since Jaffe (1868, 1869) 1961). Sjostrand (1949) demonstrated that this is described urobilin. It would manifestly be an imposi- lost as CO, an important observation not yet tion on your patience if I were to attempt any com- exploited to any extent by clinical investigators. It is prehensive treatment of the ensuing history of this intriguing that the opening of the porphyrin ring to topic, but I shall strive to bring together for you a form bile pigment involves only the ix bridge carbon. few of what seem to me the more important mile- A number of years ago Schwartz and I (Watson and stones in their relation to recent studies. For reasons Schwartz, 1942) converted the bilirubins from each that will become apparent, the term urobilin, both of a series of human fistula biles to urobilinogen, on historical and clinical chemical grounds, is best thence to a crystalline urobilin, which was shown to applied to a group of closely related substances. be the same in all instances, i.e., 9, ax in type. Gray, Under ordinary circumstances the urobilin group is Nicholson, and Nicolaus (1958) at King's College related mainly to destruction of the haemoglobin of Hospital, using a much more elegant and precise circulating red cells. Other possible sources will be method depending on oxidation to monopyrrolic referred to later. Jaffe in 1868 was not in a position compounds, have recently shown that naturally to relate his newly discovered urobilin to haemo- occurring bile pigments are uniformly 9, ix in type. globin catabolism as at that time definite evidence There are 15 possible protoporphyrin isomers, type 9 one of several was lacking that bile pigments were derived from being corresponding in configuration copyright. haemoglobin. While Virchow (1847) had suspected to the aetioporphyrin III series. that the 'haematoidin' which he found in old Biliverdin stands closest in structure to protopor- haemorrhages was identical with bilirubin, this was phyrin and there is no reason to doubt, in accord- doubted by others, especially by Stadeler (1864) who ance with Lemberg's (1955) emphasis, that it is the first crystallized bilirubin and named it. Actually it primary or mother bile pigment. It is readily reduced was not until 1923 that this question was settled by to bilirubin by mild agents such as dithionite or Hans Fischer and Reindel whose careful crystallo- ascorbic acid; however, this reduction in vivo has http://jcp.bmj.com/ graphic comparison of haematoidin and bilirubin been shown by Lemberg to be enzymatic and the clearly established their identity. Long before this enzyme 'biliverdin reductase' has recently been Tarchanoff, in 1874, had shown that haemoglobin partially purified by Singleton and Laster (1961). The given intravenously in dogs with bile fistulae results further conversion of bilirubin to mesobilirubin and in proportional increase of bilirutin in the bile. It is the urobilinogen group requires more strenuous now generally accepted that the conversion ofhaemo- reduction in vitro and can only be achieved in part. globin to bilirubin is readily effected by a highly As I shall discuss later, the reduction in vivo to meso- on September 29, 2021 by guest. Protected specific enzymatic activity A hich is v idespread but bilirubin and beyond probably depends entirely on probably limited to certain tynes of cells, especially bacterial activity, quite in accord with the belief those of mesenchymal or reticJloendothelial type. advanced by Maly (1871, 1872) only three years after Many other mammalian systems as, for example, Jaffe described urobilin. Maly reduced bilirubin that lining the gastrointestinal tract, do not elaborate partially with sodium amalgam, obtaining what he this en7yme which has recently been partially purified called 'hydrobilirubin', subsequently shown by by Nal-a ima (1958). The primary activity in con- others to represent a mixture exhibiting 'urobilin' verting hzemoglobin to bile pigment may be defined characteristics, i.e., green fluorescence with zinc and as an o idative loss of the a methene bridge carbon an absorption band in the blue-green region of the atom of the haemoglobin protoporphyrin, a spectrum. haemoglobin-haptoglobin complex, being the specific It may now be desirable to bring together briefly substrat- (Yamaguchi, Nakajima, and Yamaoka, the essential information on the composition of the urobilin group. Van Lair and Masius in 1871 'The Thomas Young lecture given at St. George's Hospital Medical School, London, on 15 February 1962. described the faecal stercobilin, noting its similarity with 2Supported by a grant from the Research and Development Com- Jaffes urobilin, but leaving open the question mand, Sutg cn General's Office, United States Army. of identity. It gradually became recognized, as a 1 J Clin Pathol: first published as 10.1136/jcp.16.1.1 on 1 January 1963. Downloaded from 2 C. J. Watson result of the work of Le Nobel (1887), Saillet (1897), is difficult to understand why he believed it was and Neubauer (1903) that these substances in both derived from urochrome. urine and faeces were excreted mainly as colourless The failure of Hopkins and Garrod and of Hans chromogens. In 1911 Hans Fischer carried Maly's Fischer, as well as many others, to isolate a crystal- amalgam reduction of bilirubin to completion and, line urobilin or stercobilin might well have dis- employing the Ehrlich aldehyde reaction (1901) to couraged further effort in this direction. But I must follow concentration of the resulting colourless admit to a number of unsuccessful attempts of my chromogen, succeeded in crystallizing a well-defined own during the late twenties. In these I followed in chemical individual which he eventually named the main the valuable procedure of Terwen in mesobilirubinogen. Fischer and Meyer-Betz (1911) Amsterdam (1925) which in retrospect would have soon demonstrated that this was identical with a permitted crystallization with but slight additional crystalline urobilinogen obtained from the urine in purification. Becausz of previous failures on this a case of hepatic cirrhosis. The question remained score I first attempted, while in Hans Fischer's whether this was the only urobilinogen and whether laboratory in 1930-32, to isolate the principal identical with the stercobilinogen of the faeces. This Ehrlich reacting chromogen ofhuman faeces in order was of practical as well as basic interest, especially to determine its identity or lack of identity with in relation to quantitative estimation in the excreta, mesobilirubinogen. Despite the use of many alterna- in the study of liver function, jaundice, and haemo- tive procedures and many kilograms of faeces, lytic disease. especially from individuals with haemolytic jaundice, From Jaffe and Van Lair and Masius onward, this attempt was also unsuccessful. By good fortune, many unsuccessful attempts were made to crystallize however, it led indirectly to the isolation of crystal- urobilin from urine or stercobilin from faeces. The line stercobilin (Watson, 1932a and b, 1933a and b, most detailed perhaps were those of Garrod and 1934, 1935a and b). This was first observed in a Hopkins (1896) and of Hopkins and Garrod (1898) solution which had been set aside for several days and of Hans Fischer (1911), but there is little doubt because of its content of a violet substance later that earlier workers, notably MacMunn and Thudi- identified for the first time in the excreta as meso- copyright. chum, were keenly interested in this problem. Let me biliviolin (Watson, 1932b; 1933a and b), which pause to pay tribute to the memory of Thudichum Fischer and Niemann (1924) had previously prepared who was Lecturer in Natural Philosophy, later by dehydrogenation of mesobilirubinogen. The Professor of Chemistry in the old St. George or stercobilin crystals first appeared as brown feathery Grosvenor Place School of Medicine during the masses, but on recrystallization from chloroform as period 1855-63. I am the proud possessor of a first orange-yellow prisms. These gave intense green http://jcp.bmj.com/ edition of his 'Pathology of the urine' (1858) which, accordingly, must have been written during his fluorescence with alcoholic zinc acetate, and the tenure in that school. As you well know, Thudichum characteristic urobilin type absorption band, maxi- is often spoken of as the 'father of brain chemistry' mum at about 492 m,u. It was now possible to show (Drabkin, 1958) but his contributions to the chemis- that this stercobilin differed from urobilin immedi- try of human urine are in many ways just as notable. ately derived by dehydrogenation of mesobiliru- In 1858 he spoke of 'urohaematine' and 'uroerythrin', binogen. The colourless, Ehrlich-reacting sterco- neither of which were well defined. In 1864 his classic bilinogen could not and has not yet been crystallized. on September 29, 2021 by guest. Protected paper 'Urochrome: the colouring matter ofurine' ap- Strenuous oxidation of mesobilirubinogen or its peared. This term superseded 'urohaematine' and has urobilin gave methyl ethyl maleininimide; that of ever since designated the normal pigment complex stercobilin did not. The latter is strongly laevo- of the urine. It seems reasonable to believe that his rotatory (Fischer, Halbach, and Stern, 1935), the 'uroerythrin' included some fraction of the urinary former optically inactive. A suitable method was 'urobilin' which Jaffe was not to describe until ten found for crystallization of the inactive or i-urobilin years later. Thudichum mentions that the largest (Watson, 1935a and b) and this has recently been amounts were noted in cases of liver disease and improved to permit direct preparation from bilirubin there is little doubt that these urines contained exces- (Watson, 1953).
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