Hepatic biotransformation in rodents and physicochemical properties of 23(R)-hydroxychenodeoxycholic acid, a natural alpha-hydroxy bile acid.
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.
Merrill
J R
JR
Division of Gastroenterology, University of California, San Diego, La Jolla 92093-0813, USA.
Schteingart
C D
CD
Hagey
L R
LR
Peng
Y
Y
Ton-Nu
H T
HT
Frick
E
E
Jirsa
M
M
Hofmann
A F
AF
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport; D001711:Biotransformation; D001944:Breath Tests; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D004372:Ducks; D008099:Liver / Q000378:metabolism*; D008297:Male; D008647:Mesocricetus; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
C099234:23-hydroxychenodeoxycholic acid; D002635:Chenodeoxycholic Acid