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Pigments. I. the Anabolic Significance of the Fecal Mesobilifuscin

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Pigments. I. the Anabolic Significance of the Fecal Mesobilifuscin STUDIES OF THE DIPYRRYLMETHENE (“FUSCIN”) PIGMENTS. I. THE ANABOLIC SIGNIFICANCE OF THE FECAL MESOBILIFUSCIN A. Sigrid Gilbertsen, … , Violet Hawkinson, C. J. Watson J Clin Invest. 1959;38(7):1166-1174. https://doi.org/10.1172/JCI103892. Research Article Find the latest version: https://jci.me/103892/pdf STUDIES OF THE DIPYRRYLMETHENE ("FUSCIN") PIGMENTS. I. THE ANABOLIC SIGNIFICANCE OF THE FECAL MESOBILIFUSCIN * By A. SIGRID GILBERTSEN, PAUL T. LOWRY, VIOLET HAWKINSON AND C. J. WATSON (From the Department of Medicine, University of Minnesota Hospital, Minneapolis, Minn.) (Submitted for publication September 15, 1958; accepted March 12, 1959) In the study of bile pigments relatively little at- Although the color of normal feces is probably tention has been given to the "fuscin" category. dependent in considerable measure on the pres- Siedel and co-workers (1-3) have contributed ence of the intensely colored "fuscin" pigments, much of the information available about these com- their significance in hemoglobin metabolism has pounds. The term bilifuscin was first used by remained a matter of speculation. Since meso- Stideler (4) to describe a dark brown pigment bilifuscin can be obtained in vitro by oxidation observed during isolation of bilirubin from cattle of bilirubinoid compounds, the corresponding fecal gallstones. Siedel has shown that this is a dipyr- pigment has been assumed to be a product of he- rylmethene resulting from halving of the (tetra- moglobin breakdown. Technical difficulties have pyrrylmethene) bilirubin molecule, each half re- discouraged attempts to clarify this question. taining one of the vinyl (CH = CH2) groups Siedel and Moller (1) described a method of puri- characterizing bilirubin. According to Siedel and fication of mesobilifuscin from feces, but it is clear M6ller (1), mesobilifuscin, as found in the feces that this included varying amounts derived- by or obtained by oxidation of mesobilirubinogen. is (artifactual) schism of bilirubinoids during the the analogous compound in which the vinyl groups procedure. This is considered again in the follow- have been reduced to ethyl groups. Theoretically, ing. mesobilifuscin could be formed by schism of bili- The present study was undertaken to determine rubin and subsequent reduction of the resulting the significance of mesobilifuscin in respect to he- bilifuscin, or by primary reduction of bilirubin to moglobin metabolism by means of N15 labeled its meso-derivatives and subsequent schism. This glycine. assumes only a catabolic origin and it is also quite conceivable that dipyrrylmethene pigments of MATERIAL AND METHODS mesobilifuscin type might be elaborated during Four individuals were studied using N1" glycine ac- the anabolic sequences of heme metabolism. cording to well established methods (7, 8). The first, Siedel, Stich and Eisenreich (3) have empha- C. B., a 55 year old male, was studied eight months after sized that mesobilifuscin occurs normally in the a left radical nephrectomy and splenectomy for hyper- feces partly as a dark brown pigment and partly nephroma. No known hematologic disease existed. as a colorless chrotnogen which is readily con- The second case, J. P., was a 65 year old male with congenital hemolytic anemia. Mention of this patient was verted to the pigment by heat and acidification. previously included in studies describing the isolation Mesobilifuscin does not have a distinct absorption of crystalline N' bilirubin from feces and demonstrating band but exhibits diffuse absorption below 500 conversion of N" labeled mesobilirubinogen to sterco- mpu. It has not been crystallized. It is readily bilin by fecal bacteria (9, 10). Case 3, L. H., a 54 year as a zinc complex from alcoholic solu- old female, was a patient with sporotrichosis and reticu- precipitated loendotheliosis. Despite an eventual fatal outcome the tion. Similar properties characterize the amor- patient's condition was relatively good at the time of the phous dark brown pigment accompanying sterco- present study; there was no evidence of hemolytic anemia. bilin in the feces and first designated as copro- The fourth subject, S. G., a 29 year old female, was a nigrin (5, 6). normal volunteer. Thus three of the four subjects stud- ied had normal or relatively normal hemoglobin metabo- * Aided under contracts with the Surgeon-General's lism. The life span of the erythrocytes approximated Office, United States Army and the Atomic Energy 120 days on the basis of the hemoglobin protoporphyrin Commission. N" data. 1166 ANABOLIC SIGNIFICANCE OF FECAL MESOBILIFUSCIN 1167 Glycine was prepared by the method of Schoenheimer TABLE I and Ratner (11) from potassium phthalimide containing Comparison of N'5 concentration in fecal stercobilin and 33 atom per cent excess N'5 for the first three cases and mesobilifuscin in subjects with normal hemoglobin metabolism, at the time of the early and 62 atom per cent excess for the fourth (normal) sub- late stercobilin N'5 peaks ject. All four were given 20 Gm. protein diets for sev- eral days before and during the period of glycine ad- Atom per cent excess in ministration. The labeled glycine was fed in total quan- Fecal tities of 15 Gm. to the normal subject and 53 Gm. to the Hemo- Fecal dipyrryl- globin sterco- methene three others. It was given over a three day period with Day after proto- bilin or or meso- equal doses at hourly intervals, except for triple doses at Case glycine N's porphyrin urobilin bilifuscin midnight and 3 a. m. according to the schedule of 1 2 0.007 0.382 0.309 Shemin and Rittenberg (7). Blood specimens were 3 1-4 0.049 0.651 0.666 drawn at one to four day intervals for the first 16 days 3 5-8 0.239 0.182 and at irregular intervals thereafter. Feces were col- 4 3-4 0.028 0.374 0.693 lected continuously for the first several weeks and were 4 5-6 0.242 0.573 0.391 divided into either two or four day periods. After five 1 133-134 0.111 0.202 0.024 weeks of study the collections were sporadic in Cases 1 3 128-129 0.072 0.200 0.057 and 3. The exact periods of collection for Cases 1, 2 and 4 117-120 0.248 0.987 0.126 4 are shown in Figures 1, 2 and 3, and for Case 3 in Table I . The hemoglobin protoporphyrin and fecal stercobilin d-urobilin and bilirubin rather than stercobilin were were crystallized according to methods previously de- isolated, by methods previously described (9, 13). The scribed (12, 13). The alcohol-Al,0,-water modifica- method used for obtaining mesobilifuscin in the first .ion (13) was used for the isolation of stercobilin. Case three cases provided a relatively crude material as com- 2 (J. P., Figure 2) had been given TerramycinO for pared with the modification of Siedel and M6ller's seven days prior to administration of glycine; hence method (1) employed in Subject 4. The dark brown or 'I' z o-5 0 LA 0 15 30 45 b0 75 90 105 120 135 ISO 1L5 180 D y s FIG. 1. N" CONCENTRATION IN CIRCULATING HEMOGLOBIN PROTOPORPHYRIN, FECAL STERCOBILIN AND FECAL MESOBILIFUSCIN IN SUBJECT No. 1 (NORMAL ERYTHROCYTE LIFE SPAN) Determinations of stercobilin and mesobilifuscin were performed on 24 hour collections of feces during the first 16 days and on 48 hour feces collections thereafter. 168 GILBERTSEN, LOWRY, HAWKINSON AND WATSON almost black precipitate appearing at several stages dur- cedure for isolation of mesobilifuscin (ogen) from feces. ing the isolation of stercobilin or bilirubin by earlier Most of the fecal samples from Subject 4 were first sub- methods (5, 9, 14) was precipitated by zinc from an al- jected to the ferrous hydroxide method for stercobilin coholic (zinc acetate) solution in the same manner as isolation as previously described (13). With two of the previously described for copronigrin. As will be noted samples (Days 33 to 36 and 41 to 44) the alternative al- in the following, the nitrogen content of the samples thus cohol-A120O5-water method (13) was used. In either obtained was considerably lower than the theory for event the aqueous filtrate or eluate was extracted re- mesobilifuscin or any pure dipyrrylmethene. In all of peatedly at pH 4.0 with petroleum ether (30 to 600 B. P.) these the nitrogen determinations were made on the zinc in order to remove most or all of the urobilinogen precipitated material; hence the low values are due at group. This was converted in the usual way (13) to the least in part to zinc which may have been present in ex- urobilin group and crystallized for N' analysis. The re- cess. Certain of the more important samples, in point maining aqueous solution, after petroleum ether extrac- of time, were analyzed for zinc 1 by the method of Vallee tion, was heated to 800 C. on a boiling water bath and and associates (15, 16). These and certain other sam- allowed to stand overnight. This results in conversion ples were also recycled according to Siedel and M6ller's of colorless chromogen to pigment. The next day it was method after which ordinary and isotopic nitrogen per- extracted three times with butyl alcohol containing 2 centages were again determined.2 per cent acetic acid; approximately 75 ml. of butyl alco- The method used in the fourth or normal subject hol was used for each extraction. The aqueous fraction (S. G.) was a modification of Siedel and M6ller's pro- was then discarded. The butyl alcohol fraction was washed three times with water and filtered through a 1 The zinc determinations were carried out by Miss Margaret Giebenhain in the Research Laboratory of the Organic Chemistry, University of Minnesota, or in the Department of Obstetrics and Gynecology, through the Clark Microanalytical Laboratory, Urbana, Illinois.
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