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Bile Acid N-Acetylglucosaminidation

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Bile Acid N-Acetylglucosaminidation Bile Acid N-Acetylglucosaminidation In Vivo and In Vitro Evidence for a Selective Conjugation Reaction of 7ft-Hydroxylated Bile Acids in Humans Hanns-Ulrich Marschall,*" Heidrun Matem,* Hubertus Wietholtz,* B6rje Egestad,t Siegfried Matem,* and Jan Sj~vall* *Department ofInternal Medicine III, Aachen University of Technology, D-5100 Aachen, Germany; and tDepartment ofPhysiological Chemistry, Karolinska Institutet, 5-10401 Stockholm, Sweden Abstract Introduction The aim of this study was to define whether N-acetylglucos- The metabolism ofbile acids in humans includes various conju- aminidation is a selective conjugation pathway of structurally gation reactions. Besides aminoacyl amidation with glycine or related bile acids in humans. The following bile acids released taurine (1) and sulfation (2), three glycosidic conjugation path- enzymatically from N-acetylglucosaminides were identified: ways have been established both in vivo and in vitro during the 3a,7,8-dihydroxy-5,j-cholanoic (ursodeoxycholic), 3#,7,6-dihy- last years: glucuronidation (3, 4), glucosidation (5, 6), and N- droxy-5ft-cholanoic (isoursodeoxycholic), 3,8,7#-dihydroxy- acetylglucosaminidation (7, 8). Semiquantitative estimates in- 5a-cholanoic (alloisoursodeoxycholic), 303,7fl-dihydroxy-5- dicated a similar urinary excretion rate for the three glycosidic cholenoic, 3a,7,B,12a-trihydroxy-5fl-cholanoic, and 3a,6a,7f- conjugates, at least in healthy humans (6, 7, 9, 10). trihydroxy-5,8-cholanoic acids. The selectivity of conjugation The present paper gives data on urinary bile acid glycosides was studied by administration of 0.5 g ursodeoxycholic after oral administration of '3C-labeled chenodeoxycholic (UDCA) or hyodeoxycholic (HDCA) acids, labeled with 13C, to (CDCA),' ursodeoxycholic (UDCA), and hyodeoxycholic patients with extrahepatic cholestasis, and of 0.5 g of '3C-la- (HDCA) acids to patients with cholestatic liver diseases. The beled chenodeoxycholic acid (CDCA) to patients with extra- or results illustrate the structural preferences of the different gly- intrahepatic cholestasis. After administration of [24-'3q- cosidation pathways. Determinations of structures of bile acids CDCA, labeled glucosides, and the glucuronide of CDCA were conjugated in vivo together with enzymatic data in vitro pro- excreted in similar amounts. Labeled N-acetylglucosaminides vide evidence for a selective conjugation of 7f3-hydroxylated of UDCA and isoUDCA were also formed. When I24-Cl~- bile acids like UDCA with N-acetylglucosamine. This selective UDCA was given, "3C-label was detected in the N-acetylglu- metabolic pathway may help to explain the mechanism of the cosaminide, the glucosides, and the glucuronide of UDCA, and beneficial effect of UDCA in patients with cholestatic liver dis- in the N-acetylglucosaminide of isoUDCA. In the patient stud- eases. ied, 32% of the total UDCA excreted in urine was conjugated with N-acetylglucosamine. In contrast, 96% of the excreted Methods amount of [24-'3CHDCA was glucuronidated, and 'IC-labeled Materials. The sources and the purity of most materials are described glucosides but no N-acetylglucosaminide were detected. The elsewhere (10, 1 1). Alloursodeoxycholic acid and methyl-3,7-diketo- selectivity of N-acetylglucosaminidation towards bile acids 5a-cholanoate were kind gifts of Drs. H. lida (Nihon University, Fuku- containing a 7,8-hydroxyl group was confirmed in vitro using shima, Japan) and W. H. Elliott (St. Louis University Medical School, human liver and kidney microsomes and uridine diphosphate St. Louis, MO), respectively. Isoursodeoxycholic acid synthesized by glucose Dr. F. C. Chang was obtained from Dr. Bader's Library of Rare Chemi- (UDP)-N-acetylglucosamine. These studies show that cals Chemical N-acetylglucosaminidation is a selective (Aldrich Co., Milwaukee, WI). [24-'3CJCDCA, [24- conjugation pathway '3C]UDCA, and [24-'3C]HDCA acids were synthesized in a modifica- for 78-hydroxylated bile acids. (J. Clin. Invest. 1992.89:1981- tion (12) of the method by Tserng and Klein (13), giving a 13C excess of 1987.) Key words: ursodeoxycholic acid * glucosidation * glu- 89±2 atom %, calculated (14) from the main fragment ions containing curonidation * gas chromatography-mass spectrometry * stable the side chain. isotope labeling Structure analysis of bile acid N-acetylglucosaminides. Extraction, purification, and characterization of bile acid N-acetylglucosaminides was performed using modifications ofpreviously described methods (7, 11). A flow scheme is shown in Fig. 1. In short, total bile acids were extracted from multiple 24 h collections of urine with Sep-Pak octa- Preliminary data of this study were presented at the 32nd IUPAC Con- decylsilane-bonded silica (C18) cartridges and separated by anion ex- gress, 2-7 August, 1989, Stockholm, Sweden, at the XI International change chromatography on Lipidex-diethylaminohydroxypropyl Bile Acid Meeting, 1 1-13 October, 1990, Freiburg, Germany, and at (DEAP). A known amount of [24-'4C]cholic acid was added to urine to the 41st Annual Meeting of the AASLD, 3-6 November, 1990, Chi- monitor separations and recoveries. The first fraction containing un- cago, IL. conjugated bile acids and nonamidated bile acid glucosides and N-ace- Address correspondence to Dr. Hanns-Ulrich Marschall, Medizin- ische Klinik III, Klinikum der RWTH, Pauwelsstrasse 30, D-5 100 Aa- 1. Abbreviations used in this paper: alloisoUDCA, alloisoursodeoxy- chen, Germany. cholic acid; alloUDCA, alloursodeoxycholic acid; CDCA, chenodeoxy- Receivedfor publication 27 August 1991 and in revisedform 3 De- cholic acid; C18, octadecylsilane-bonded silica; DEAP, diethylamino- cember 1991. hydroxypropyl; FABMS, fast atom bombardment mass spectrometry; GC/MS, gas chromatography-mass spectrometry; HDCA, hyodeoxy- J. Clin. Invest. cholic acid; isoUDCA, isoursodeoxycholic acid; M/Z, mass/charge ra- © The American Society for Clinical Investigation, Inc. tio; RI, retention index; 7-epiCA, 7-epicholic acid; 7-epiHCA, 7-epi- 0021-9738/92/06/1981/07 $2.00 hyocholic acid; TMS, trimethylsilyl; UDCA, ursodeoxycholic acid; Volume 89, June 1992, 1981-1987 UDP, uridine diphosphate glucose. N-Acetylglucosaminidation of 7,8-Hydroxy Bile Acids 1981 Patients studied. Clinical and relevant routine laboratory data are given in Table I. One patient (A) with intrahepatic cholestasis due to SEP-PAK EXTRACTION alcoholic liver disease and another patient (B) with extrahepatic chole- stasis were given 0.5 g of [24-'3C]CDCA. Two other patients with extra- hepatic cholestasis obtained 0.5 g of [24-'3C]UDCA (C), and [24-'3C]- HDCA (D), respectively. Informed consent was given by all patients. The study was carried out in accordance with the Helsinki Declaration LIPIDEX-DEAP II and was approved by the local ethics committee. Analysis of bile acids in urine after oral administration of'3C-la- beled bile acids. Total bile acids were extracted from 24-h collections of urine by repetitive use of Sep-Pak C18 cartridges. Group separation of bile acids by anion-exchange chromatography on Lipidex-DEAP was LIPIDEX 5000 performed by a modification ofthe original method of Alme et al. (17) for the estimation of glycosidic bile acid conjugates (10). Three frac- tions are obtained: (a) unconjugated bile acids and nonamidated bile acid glucosides and N-acetylglucosaminides; (b) glycine- or taurine- conjugated bile acids and glycine- or taurine-conjugated bile acid glu- cosides; and (c) bile acid glucuronides. In addition, a fraction (d) con- REVERSED-PHASE HPLC taining bile acid mono- and disulfates, was collected by elution with 15 --MEMO I ml 0.3 M ammonium acetate, pH 9.6, in 70% ethanol (17). Fraction (b) was treated with cholylglycine hydrolase yielding deamidated bile acids and bile acid glucosides (10), and fraction (c) was hydrolyzed with cho- lylglycine hydrolase and the digestive juice of Helix pomatia yielding ENZYMATIC HYDROLYSIS deamidated and deglucuronidated bile acids (GlcA in Table II). Frac- M.I tion (d) was solvolysed with trifluoroacetic acid in tetrahydrofuran (18) I and treated with cholylglycine hydrolase (Sulfates in Table II). After extraction with Sep-Pak C18 and methylation, fractions (a) and (b) were further subfractionated on Lipidex 5,000 with chloroform/hexane 1:4- HPLC 1:1 (vol/vol) (19), yielding unconjugated bile acids, bile acid glucosides, STRAIGHT-PHASESTRA~~~~~~~~~~~~ and N-acetylglucosaminides from fraction (a) (Uncon, Glc, and GlcNAc in Table III), and deamidated bile acids and deamidated bile Figure 1. Flow scheme acid glucosides from fraction (b) (G/T and G/T-Glc in Table II). The for the characterization methyl esters ofbile acid N-acetylglucosaminides were hydrolyzed with GAS CHROMATORAPHY of bile acid N-acetylglu- N-acetylglucosaminidase as described above. After conversion to TMS MASS SPECTROMETRY| cosaminides from hu- ether derivatives, nonamidated and amidated glucosides (Glc and G/T- man urine. Glc) were analyzed by GLC and GC/MS using column A, while both columns A and B were used for all other fractions (Uncon, GlcNAc, G/T, GlcA, and Sulfates). GLC and mass-spectrometry. GLC, GC/MS, and fast atom bom- tylglucosaminides was eluted with 0.1 M acetic acid in 70% ethanol and bardment mass spectrometry (FABMS) were performed using the methylated with diazomethane. Methyl esters of unconjugated bile equipment and conditions previously described (I 1). Column A was a acids were removed on Lipidex 5000 yielding a fraction containing bile 24 m X 0.32 mm ID fused silica capillary coated with crosslinked acid glucosides
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