Merrill, JR and Schteingart, CD and Hagey, LR and Peng, Y and TonNu, HT and Frick, E and Jirsa, M and Hofmann, AF (1996) Hepatic biotransformation in rodents and physicochemical properties of 23(R)-hydroxychenodeoxycholic acid, a natural alpha-hydroxy bile acid. JOURNAL OF LIPID RESEARCH, 37 (1). pp. 98-112. ISSN 0022-2275,
Full text not available from this repository.Abstract
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-C-14]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 (CO2)-C-14. Radioactivity in bile was present as unchanged compound (25-50%, dose-dependent) and its conjugates (with taurine, with glycine, or with glucuronate). Nor-CDCA (C-23) 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 cr-oxidation (10 +/- 2%). Nor-CDCA also underwent 6 beta-hydroxylation to form nor-alpha-muricholic acid, as well as reduction of its C-23 carboxyl group to form the C-23 alcohol. The taurine conjugate of 23(R)OH-CDCA [23(R)OH-CDC-tau] was prepared synthetically and characterized by H-1-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 3 alpha,7 alpha-dihydroxy bile acid alters its metabolism in the rodent hepatocyte, as evidenced by inefficient conjugation with taurine or glycine, alpha-oxidation to nor (C-23) bile acid, and reduction of the nor bile acid to the primary alcohol. The murine 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 C-23 nor-bile acids may be formed by alpha-oxidation of alpha-hydroxy C-24 bile acids.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BETA-PHOCAECHOLIC ACID; SIDE-CHAIN; ENTEROHEPATIC CIRCULATION; URSODEOXYCHOLIC ACID; CHOLYLGLYCINE HYDROLASE; PHARMACOKINETIC MODEL; RAT-LIVER; TRANSPORT; METABOLISM; IDENTIFICATION; alpha-oxidation; bile acid deconjugation; bile acid metabolism; critical micellization concentration; critical micellization pH; bile alcohols |
| Depositing User: | Dr. Gernot Deinzer |
| Last Modified: | 19 Oct 2022 08:36 |
| URI: | https://pred.uni-regensburg.de/id/eprint/52083 |
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