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Coproporphyrin III Is Regularly Excreted In CONCERNING THE NATURALLY OCCURRING PORPHYRINS. IV. THE URINARY PORPHYRIN IN LEAD POISONING AS CON- TRASTED WITH THAT EXCRETED NORMALLY AND IN OTHER DISEASES' By CECIL JAMES WATSON (From the Department of Medicine, University of Minnesota Hospital, Minneapolis) (Received for publication January 22, 1936) In previous communications (1, 2, 3), the lit- The concept that the coproporphyrin of the erature relating to H. Fischer's "dualism'" of urine and bile is derived from hemoglobin was the natural porphyrins was discussed. The isola- not supported by the findings described in Parts I tion of coproporphyrin I from the urine of a pa- to III of this investigation (1, 2, 3). The occur- tient with cincophen cirrhosis of the liver, also rence of coproporphyrin I rather than III consti- from the feces in hemolytic jaundice and perni- tuted evidence that at least in the instances stud- cious anemia, was reported. Of particular in- ied, porphyrin formation was a process distinctly terest was the consideration of these findings with separate from the synthesis or destruction of relation to the clinical and experimental observa- hemoglobin. The isolation of coproporphyrin III tions of Van den Bergh and coworkers (4, 5). from the urine in lead poisoning was described by These investigators pointed out that human eryth- Grotepass (9), later by H. Fischer and Duesberg rocytes regularly contain protoporphyrin which is (10). Since ordinary hemin and coproporphyrin increased in amount in the same individuals who III both correspond in configuration to aetiopor- exhibit increases of coproporphyrin in the urine. phyrin III, the elaboration of coproporphyrin III By perfusion experiments they further demon- in lead poisoning could be associated quite readily strated that the surviving liver of the dog is able a disturbance in hemoglobin metabo- to convert protoporphyrin into coproporphyrin. with peculiar Correlation.of these studies made it appear likely lism. that the coproporphyrin of the urine, as well as of The function of the porphyrins present in the the bile, may originate from the protoporphyrin erythrocytes, urine, bile and feces is quite un- of the erythrocytes. Since hemoglobin, following known and can hardly be determined until exact loss of its protein and iron, yields a protoporphy- knowledge of their origin and isomeric type is rin of the aetioporphyrin III type (6), it was obtained. The amount of porphyrin in normal naturally assumed that the porphyrins of the urine urine is so small that it has not yet been isolated, and bile are directly related to hemoglobin metab- and the important question as to whether it is olism. Schreus (7) in particular has pointed to coproporphyrin I or III remains unanswered. Van den Bergh's results as supporting this con- The finding of coproporphyrin I in the urine in ception. The idea that the porphyrin of the urine an instance of advanced liver disease (1), sug- is derived from hemoglobin is by no means a re- gested that it was the normal urine porphyrin, in- cent one. In fact, a considerable literature deal- creased in amount for the same reason that uro- ing with this question was collected by Garrod in bilinogen was increased, i.e., diminished excretory 1900 (8). Although Garrod subscribed to the function of the liver. belief that the urinary porphyrin, then spoken of The purpose of the present investigation was to as hematoporphyrin, was related to hemoglobin isolate and identify the coproporphyrin of a nor- destruction, he observed that increases in amount mal urine, and of the urine in some of the patho- were frequently associated with clinical or ana- logical states accompanied by a heightened por- tomical evidence of liver disease. phyrin excretion; further, to determine whether coproporphyrin III is regularly excreted in the 1Aided by a grant from research funds of the Graduate urine in lead poisoning (as yet it has been isolated School of the University of Minnesota. but from one instance). 327 328 CECIL JAMES WATSON MATERIAL AND METHODS Hemoglobin was 32 per cent (Sahli), erythrocytes 1,150,-' 000 per cu. mm. Stained smears revealed marked macro- The entire amount of urine for a period of 33 anisocytosis, polychromatophilia. Reticulocytes varied days was collected from a healthy male student 2 between 15 and 32 per cent. Resistance of erythrocytes 18 years of age. As soon as 2 to 3 liters had to hypotonic saline was as follows: H1 .38, H, .32, control accumulated the specimen was subjected to the H, .38, H2 .30. procedure previously described (1), with the fol- There was marked autoagglutination of erythrocytes in vitro (below 300 C.), the icterus index was 30, and the lowing exceptions. In each instance the primary Van den Bergh reaction was of the indirect type. Feces ether extract after washing with water was re- urobilinogen: 1106 mgm. per day. (Normal range 100 peatedly extracted with small amounts of 10 per to 250.) Urine urobilinogen 2.5 mgm. per day. (Nor- cent HCl. The 10 per cent HC1 solutions were mal range 0.5 to 3.0.) (23) united and kept in the refrigerator during the Physical examination revealed nothing except a smooth cystic mass in the left side of the pelvis. The spleen and period of further collection and primary extrac- liver were not palpable. It was considered possible that tion of the urine. All of the hydrochloric acid chronic hemorrhage into an ovarian cyst with local for- extract was then covered with a large amount of mation of bilirubin might be responsible for the findings ether, an excess of sodium acetate was added, and described above. Consequently the cyst was removed at the mixture at once vigorously shaken. Having operation. It contained 800 cc. of a dark brown fluid rich in hematin (identified by hemochromogen spectrum made certain that the aqueous fraction was nega- after treatment with ammonium sulphide). Bilirubin and tive to Congo paper, ether extraction was re- porphyrins were not identified, although searched for. peated until the porphyrins were removed com- There was no improvement following this operation. pletely. The further treatment of this solution On the contrary, icterus and anemia increased, and there of ether was the same as described previously was moderate fever. The urobilinogen in the urine in- (1). The final coproporphyrin solution in ether creased markedly for a few days after operation, then decreased rapidly again. The highest value noted was was not dried over sodium sulphate as was done 380 mgm. per day. During this period the urine was previously, since it has been found to be true that examined for porphyrins and a considerable increase of a moderate loss of porphyrin occurs by adsorption coproporphyrin was observed. on this salt. This was first noted by H. Fischer After an interval of three weeks during which the pa- and Zerweck (11). The ether was simply de- tient's condition remained precariously stationary, sple- nectomy was carried out. The spleen weighed but 460 canted into a dry flask and was then removed com- grams, exhibiting microscopically a marked pulp conges- pletely upon the water bath. The porphyrin resi- tion. The liver appeared to be entirely normal. This due after drying in the air was esterified with operation was followed by prompt improvement. Two HCl in methyl alcohol, and the ester was crystal- months after operation the hemoglobin was 70 per cent lized from chloroform-methyl alcohol in -the usual (Sahli), the icterus index 10, and the feces urobilinogen 206 mgm. per day. Eight months later the patient re- way (1). ported that she felt entirely well and that there was no Employing the samne method, porphyrin esters jaundice. were isolated from the urines of the following The urine employed for the isolation of coproporphyrin cases. consisted of the entire amount for a period of four days immediately following the first operation (coincident with Case 1. Fever. Male, 37 years of age with lung the highest urobilinogen excretion). This urine was first abscess and empyema. The daily elevation of tempera- employed for the isolation of crystalline urobilinogen, a ture ranged from 101 to 1030 F. Urobilinuria was 8.3 procedure which will be described elsewhere (24). Suf- mgm. urobilinogen per day (23). Therewasno jaundice. fice it to say that this entailed a preliminary extraction Moderate anemia was present, and hemoglobin was 55 per with petroleum ether in which coproporphyrin is insolu- cent (Sahli method, 17 grams per 100 cc. equivalent to ble. Following this, the coproporphyrin was extracted 100 per cent). Urine was collected for a period of 12 with ether in the manner already referred to (1). It is days. worthy of note that this urine contained another pigment resembling bilirubin, but differing from it in that it failed to a test as well as the more delicate reaction Case 2. Acquired hemolytic jaundice. Female, 18 give Gmelin years of age with slight icterus, without anemia, of 3 for bilirubin devised by Harrison, and described by God- years' duration, increasing icterus and anemia, 4 months. fried (12). Also differing from bilirubin the substance could not be extracted with chloroform from the urine. 2 The writer is indebted to Mr. Samuel Schwartz for However, it gave a delayed and an indirect Van den the collection and preliminary extraction of this urine. Bergh reaction, and was precipitated by a barium chlo- CONCERNING THE NATURALLY OCCURRING PORPHYRINS. IV 329 ride solutioni. In dilute NaOH ill defined absorption recalilbrated, these are believed attributable to between 536 to 477 mny was observed. Attempts to crys- very sliglht changes in the relation of the wave tallize the substance were unsuccessful, probably because length scale of the to its of its obvious lability, and it cani only be stated that its instrtumiient grating.
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