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Glucuronidation of 6A-Hydroxy Bile Acids by Human Liver Microsomes Anna Radominska-Pyrek,* Piotr Zimniak,* Yacoub M

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Glucuronidation of 6A-Hydroxy Bile Acids by Human Liver Microsomes Anna Radominska-Pyrek,* Piotr Zimniak,* Yacoub M Glucuronidation of 6a-Hydroxy Bile Acids by Human Liver Microsomes Anna Radominska-Pyrek,* Piotr Zimniak,* Yacoub M. Irshaid,t Roger Lester,* Thomas R. Tephly,t and Jan St. Pyrek *Division of Gastroenterology, Department ofInternal Medicine, University of Texas Medical School at Houston, Houston, Texas 77225; *Department ofPharmacology, University ofIowa, Iowa City, Iowa 52242; §Department ofBiochemistry, Jzice University, Houston, Texas 77251 Abstract accumulation of cytotoxic mono- and dihydroxylated bile acids in this disease; details of this viewpoint will be discussed later. The glucuronidation of 6-hydroxylated bile acids by human liver A certain amount of disagreement exists in the literature nicrosomes has been studied in vitro; for comparison, several concerning the presence of bile acid 6a-hydroxylase activity in ,major bile acids lacking a 6-hydroxyl group were also investi- human tissues. Whereas Bjorkhem et al. (12) could not detect gated. Glucuronidation rates for 6a-hydroxylated bile acids were any appreciable hydroxylation of lithocholate, taurolithocholate, 10-20 times higher than those of substrates lacking a hydroxyl and taurochenodeoxycholate by isolated human liver micro- group in position 6. The highest rates measured were for hyode- somes in the presence of NADPH, Trulzsch et al. (6) found qxy- and hyocholic acids, and kinetic analyses were carried out conversion of taurolithocholate to taurohyodeoxycholate under using these substrates. Rigorous product identification by high- similar conditions. The lack of a 6a-hydroxylase would be, how- field proton nuclear magnetic resonance and by electron impact ever, inconsistent with the well-documented occurrence of 6a- mass spectrometry of methyl ester/peracetate derivatives re- hydroxylated bile acids in humans: no bacterial hydroxylation vealed that 6-O-jD-glucuronides were the exclusive products of bile acids is known to take place in the gut (13, 14), and formed in these enzymatic reactions. These results, together with dietary intake is likely to be negligible. Moreover, 6a-hydroxylase literature data, indicate that 6a-hydroxylation followed by 6-0- activity was reported to be inducible with phenobarbital in hu- glucuronidation constitutes an alternative route of excretion of mans (15). Thus, the emerging consensus appears to be that a toxic hydrophobic bile acids. bile acid 6a-hydroxylase activity is present in the human liver (3, 10). Introduction A major form of urinary excretion of many 6a-hydroxy bile acids is the glucuronide (4, 8) identified, in the case ofhyodeoxy- Bile acids with a hydroxyl group in position 6 of the steroidal cholic acid, as the 6-0-,#-glucuronide (2). The formation of hy- nucleus occur in several mammalian species. In pigs, 3a,6a- odeoxycholic acid glucuronide upon oral administration ofeither dihydroxycholanoic (hyodeoxycholic) acid constitutes the major the free bile acid or of its glycine conjugate to human volunteers biliary bile acid, with 3a,6a,7a-trihydroxycholanoic (hyocholic) has been studied in vivo (7); in a subsequent communication, acid occurring in smaller amounts; in the bile of rodents, several the same group of investigators reported that the reaction can 6f3-hydroxylated bile acids are present (1). Although 6a-hy- be demonstrated in vitro using either human liver or kidney droxylated bile acids can be identified in the urine of healthy microsomes (16). The reaction product was assigned the structure human subjects (2-4), as well as in meconium (5), they do not of a 3-0-glucuronide (7), at variance with data previously pub- occur in normal human bile or serum. Inasmuch as the site of lished for the urinary metabolite (2) and with our results (this bile acid 6-hydroxylation is the liver (6, but see below), the lack report). ofdetectable circulating 6-hydroxy bile acids attests to their very The purpose of the present study was (a) to expand the in rapid renal clearance, in agreement with direct experimental vitro studies of glucuronidation of 6-hydroxylated bile acids by evidence (7, 8). In pathological states, especially in cholestatic human hepatic microsomes using several representative sub- liver disease, the amount of excreted 6-hydroxylated bile acids strates of varying configuration of the molecule and number of increases, and they also become detectable in bile and serum hydroxyl groups, (b) to compare the glucuronidation of 6a-hy- (2-4, 9, 10). This correlation suggests (although it obviously does droxylated bile acids with that of the major primary and sec- not prove) that the occurrence of 6-hydroxy bile acids is either ondary human bile acids in which the glucuronyl moiety is a cause or a consequence of cholestasis. The former possibility attached to the hydroxyl group in position 3a (3a-OH), and (c) is unlikely in that no adverse effects were reported upon long- to perform rigorous spectral identification of enzymatically term (1 1) or short-term (8) administration of hyodeoxycholate. formed glucuronides of 6-hydroxylated bile acids. We interpret the formation of large amounts of 6-hydroxylated Preliminary accounts of this work were presented at the 9th bile acids in cholestasis as a response of the organism to the International Bile Acid Meeting, Basel, October 1986, and at the meeting of the American Association for the Study of Liver Diseases, Chicago, November 1986 (17). Address reprint requests to Dr. Radomin'ska-Pyrek, Division of Gastro- enterology, University of Texas Medical School, P.O. Box 20708, Hous- ton, TX 77225. Methods Received for publication 27 October 1986 and in revised form 10 March 1987. Human liver samples and microsomes. Human liver samples were ob- tained from organ donors as part of an organ transplant program. Livers J. Clin. Invest. B and C were obtained from a 25-yr-old man and a 5-yr-old girl, re- © The American Society for Clinical Investigation, Inc. spectively, killed in traffic accidents. Liver A was obtained from a 65- 0021-9738/87/07/0234/08 $2.00 yr-old woman who died as a result of a cerebrovascular accident. This Volume 80, July 1987, 234-241 patient had a history of multiple drug treatment, including mannitol, 234 Radominiska-Pyrek et al. dopamine, dexamethasone, methylprednisolone, vasopressin, hydrala- 1.5 mg/ml, respectively. The reaction was terminated by addition of an zine, and ampicillin. Histology was normal for all livers. Livers were excess of ice-cold glycine-trichloroacetic acid buffer, pH 2.8, and applying perfused briefly (flushed) with ice-cold Collin solution, dissected, and to Bond-Elut cartridges as described above. The bile acid glucuronides frozen in dry ice. The livers were stored at -70'C until used for the were further purified on preparative TLC plates, eluted, and the corre- preparation of microsomes. Microsomes were prepared as previously sponding methyl ester-acetates were prepared as described previously described (18), except that they were washed once and suspended in 0.25 (20). The resulting derivatives of bile acid glucuronides were analyzed M sucrose, 5 mM Tris-HCl, pH 7.5, and added to the incubation mixture by TLC, MS, and 'H-NMR. in this buffer. The microsomes were stored at -70'C and, in respect to MS and NMR spectrometry. Electron impact (70 and 20 eV, solid the activities studied, were stable for at least 12 mo. probe) mass spectra were obtained on Shimadzu QPIOOO (Shimadzu Materials. Nonlabeled bile acids, including hyocholic acid (3a,6a,7a- Scientific Instruments, Inc., Columbia, MD) and Extrel ELQ-400 (Extrel, trihydroxy-5,-cholanoic acid) and hyodeoxycholic acid (3a,6a-dihy- Pittsburgh, PA) mass spectrometers. Fourier-transformed 1H-NMR droxy-5fl-cholanoic acid), were obtained from Calbiochem-Behring Corp., spectra were measured at 300 MHz in CDC13 using a General Electric La Jolla, CA. 6-Epi-hyodeoxycholic acid (3ac,6l-dihydroxy-5#-cholanoic QE-300 (General Electric Co., Fremont, CA) instrument. acid) was obtained from Research Plus, Bayonne, NJ. Allohyodeoxycholic Statistical analysis. Enzyme activity measurements are reported as acid (3a,6a-dihydroxy-5a-cholanoic acid) was obtained by sodium bo- mean±standard deviation. Kinetic parameters were calculated using a rohydride reduction of 3a-hydroxy-6-oxo-5a-cholanoic acid (Research numerical version of the direct linear plot method (22-24). Plus) and separation of the resulting epimers; the identity ofthe product was confirmed by nuclear magnetic resonance (NMR) and mass spec- Results trometry (MS). The acetonide of hyocholic acid (3a-hydroxy-6a,7a-iso- Substrate specificity. The formation of bile acid glucuronides by propylidenedioxy-5fl-cholanoic acid) was synthesized using dimethoxy- microsomes was studied on liver propane (19) and characterized by NMR and MS. detergent-activated hepatic All compounds were checked for chemical purity by thin-layer chro- samples obtained from three human subjects who are described matography (TLC).' Uridine diphosphate [U-'4C`glucuronic acid (225- in more detail in the Methods section. The conditions for the 325 mCi/mmol) was from New England Nuclear, Boston, MA, or from enzymatic reaction were as reported before (20), except that ini- ICN, Irvine, CA. Uridine diphosphate glucuronic acid, ammonium salt, tially two pH values, 6.5 and 7.5, were used. Reaction rates were saccharolactone, ursodeoxycholic acid, and Brij 58 were from Sigma higher by - 30% at pH 6.5 for both deoxycholic and hyodeoxy- Chemical Co., St. Louis, MO. Bond-Elut cartridges (C18, size: 6 cm3) cholic acid, in agreement with previous findings for C24 bile were from Analytichem International, Harbor City, CA. acids (20, 25); consequently, this pH was used throughout the Enzyme assays. Bile acid substrates were prepared in the form of study. The results are summarized in Fig. 1. In the right-hand mixed micelles with Brij 58, and microsomes were activated (permea- panels of the figure, bile acids that lack a hydroxyl group in bilized) with the same detergent as previously described (20). The basic are The rates of their are reaction mixture for the determination of UDP-glucuronosyltransferase position 6 shown.
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