Journal of Lipid Research, Vol 37, 98-112, Copyright © 1996 by Lipid Research, Inc.

ARTICLES

Hepatic biotransformation in rodents and physicochemical properties of 23(R)-hydroxychenodeoxycholic acid, a natural alpha-hydroxy bile acid

JR Merrill, CD Schteingart, LR Hagey, Y Peng, HT Ton-Nu, E Frick, M Jirsa and AF Hofmann
Division of Gastroenterology, University of California, San Diego, La Jolla 92093-0813, USA.

The hepatic biotransformation in the rat and hamster of 23(R)- hydroxychenodeoxycholic acid (23(R)OH-CDCA), the alpha-hydroxy derivative of CDCA, was defined; some physiological and physicochemical properties were also assessed. 23(R)OH-CDCA was isolated from duck bile; [24-14C]23(R)OH-CDCA was synthesized. The compound was administered intravenously to anesthetized biliary fistula rats at doses of 1, 3, or 5 mu mol/kg-min and to hamsters at 3 mu mol/min-kg. Biliary bile acids and radioactivity were analyzed by thin-layer chromatography (TLC), high pressure liquid chromatography (HPLC), and gas chromatography-mass spectrometry (GC-MS). Recovery of radioactivity in bile was incomplete (50-70% of infused dose); some was also recovered as breath 14CO2. Radioactivity in bile was present as unchanged compound (25-50%, dose-dependent) and its conjugates (with taurine, with glycine, or with glucuronate). Nor-CDCA (C23) was present in bile (in both unconjugated and conjugated form), indicating that 23(R)OH-CDCA had undergone oxidative decarboxylation (alpha-oxidation) with loss of the C-24 carboxyl group. The alpha-oxidation was 20 +/- 5% (mean +/- SD) of administered dose in the rat and was not dose- dependent; in hamsters, alpha-oxidation was 35 +/- 8%. In rats, the S isomer of 23OH-CDCA also underwent alpha-oxidation (10 +/- 2%). Nor- CDCA also underwent 6beta-hydroxylation to form nor-alpha-muricholic acid, as well as reduction of its C-23 carboxyl group to form the C23 alcohol. The taurine conjugate of 23(R)OH-CDCA [23(R)OH-CDC-tau] was prepared synthetically and characterized by 1H-NMR. By surface tension measurements, it had a critical micellization concentration (CMC) of 3.5 mM (in 0.15 M Na+), as compared to 1.8 mM for CDC-taurine. Aqueous solubility of 23(R)OH-CDCA increased markedly above pH 5, compared to pH 7 for CDCA. When incubated with cholylglycine hydrolase, 23(R)OH-CDC- tau was deconjugated at a rate one-fourth that of CDC-tau. It is concluded that the presence of a 23(R)-hydroxyl group in a 3alpha, 7alpha-dihydroxy bile acid alters its metabolism in the rodent hepatocyte, as evidenced by inefficient conjugation with taurine or glycine, alpha-oxidation to nor (C23) bile acid, and reduction of the nor bile acid to the primary alcohol. The taurine conjugate of 23(R)OH- CDCA, a major biliary bile acid of marine mammals and wading birds, is a biological detergent with properties superior to those of the taurine conjugate of CDCA. Natural C23 nor-bile acids may be formed by alpha- oxidation of alpha-hydroxy C24 bile acids.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. N. V. S. Mamidi, G. Mannens, P. Annaert, J. Hendrickx, I. Goris, M. Bockx, C. G. M. Janssen, M. Kao, M. F. Kelley, and W. Meuldermans Metabolism and Excretion of RWJ-333369 [1,2-Ethanediol, 1-(2-Chlorophenyl)-, 2-carbamate, (S)-] in Mice, Rats, Rabbits, and Dogs Drug Metab. Dispos., April 1, 2007; 35(4): 566 - 575. [Abstract] [Full Text] [PDF]

				G. Kakiyama, T. Iida, T. Goto, N. Mano, J. Goto, T. Nambara, L. R. Hagey, C. D. Schteingart, and A. F. Hofmann Identification of a novel bile acid in swans, tree ducks, and geese: 3{alpha},7{alpha},15{alpha}-trihydroxy-5{beta}-cholan-24-oic acid J. Lipid Res., July 1, 2006; 47(7): 1551 - 1558. [Abstract] [Full Text] [PDF]

				F. Kannenberg, P. Ellinghaus, G. Assmann, and U. Seedorf Aberrant Oxidation of the Cholesterol Side Chain in Bile Acid Synthesis of Sterol Carrier Protein-2/Sterol Carrier Protein-x Knockout Mice J. Biol. Chem., December 10, 1999; 274(50): 35455 - 35460. [Abstract] [Full Text] [PDF]