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D22-ursodeoxycholic acid, a unique metabolite of administered ursodeoxycholic acid in rats, indicating partial b-oxidation as a major pathway for bile acid metabolism



D22-ursodeoxycholic acid, a unique metabolite of administered ursodeoxycholic acid in rats, indicating partial b-oxidation as a major pathway for bile acid metabolism



Biochemistry (American Chemical Society) 34: 69-78



We describe for the first time the identification of 3a,7b-dihydroxy-5b-chol-22-en-24-oic acid (D22-UDCA) in the plasma, bile, intestinal contents, and liver tissue of Sprague-Dawley rats after intravenous and oral administration of ursodeoxycholic acid (UDCA). Infusion of [2,2,4,4-2H4]UDCA confirmed D22-UDCA to be a specific metabolite of UDCA. Definitive confirmation of this unique and major metabolite was established by liquid secondary ionization mass spectrometry and gas chromatography-mass spectrometry by comparison of the retention index and mass spectrum with an authentic standard of D22-UDCA. When rats were fed a diet containing 1.0% UDCA, high concentrations of D22-UDCA were found in the plasma (40.3 [plus or minus] 11.8 mmol/L) and liver tissue (300.9 [plus or minus] 64.2 nmol/g of tissue), and these represented 36% and 57%, respectively, of the UDCA concentration. In animals fed 0.4% and 1.0% UDCA, the mass of D22-UDCA in the jejunum was high (7.5 [plus or minus] 0.9 and 6.6 [plus or minus] 0.6 mg, respectively), accounting for 50-60% of the total UDCA, but diminished markedly along the intestine, accounting for <3% of the total UDCA in the colon. Although D22-UDCA was not found in biological samples from control rats, D22-b-muricholic and D22-q-muricholic acids were normal constituents of plasma and intestinal contents and were major muricholate isomers in liver tissue and bile. Synthesis of D22-bile acids appears to be highly specific toward bile acids possessing a functional 7b-hydroxyl group. We presume that, in common with pathways for endogenous bile acid synthesis, partial side-chain oxidation of UDCA occurs in the peroxisome with formation of a/b unsaturation; since UDCA has only a 5-carbon side chain, release of propionic or acetic acid is not possible, b-oxidation proceeds no further, and D22-UDCA is formed. While the mechanism of formation and physiological significance of D22-bile acids remain to be established, our data indicate that partial b-oxidation is a quantitatively important pathway for endogenous bile acid synthesis and for UDCA metabolism in this species. Copyright 1995, American Chemical Society.

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