delta 22-Ursodeoxycholic acid, a unique metabolite of administered ursodeoxycholic acid in rats, indicating partial beta-oxidation as a major pathway for bile acid metabolism.
We describe for the first time the identification of 3 alpha, 7 beta-dihydroxy-5 beta-chol-22-en-24-oic acid (delta 22-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 delta 22-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 delta 22-UDCA. When rats were fed a diet containing 1.0% UDCA, high concentrations of delta 22-UDCA were found in the plasma (40.3 +/- 11.8 mumol/L) and liver tissue (300.9 +/- 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 delta 22-UDCA in the jejunum was high (7.5 +/- 0.9 and 6.6 +/- 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 delta 22-UDCA was not found in biological samples from control rats, delta 22-beta-muricholic and delta 22-omega-muricholic acids were normal constituents of plasma and intestinal contents and were major muricholate isomers in liver tissue and bile. Synthesis of delta 22-bile acids appears to be highly specific toward bile acids possessing a functional 7 beta-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 alpha/beta unsaturation; since UDCA has only a 5-carbon side chain, release of propionic or acetic acid is not possible, beta-oxidation proceeds no further, and delta 22-UDCA is formed. While the mechanism of formation and physiological significance of delta 22-bile acids remain to be established, our data indicate that partial beta-oxidation is a quantitatively important pathway for endogenous bile acid synthesis and for UDCA metabolism in this species.
Setchell
K D
KD
Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Yamashita
H
H
Rodrigues
C M
CM
O'Connell
N C
NC
Kren
B T
BT
Steer
C J
CJ
D000818:Animals; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D002793:Cholic Acids / Q000378:metabolism; D003106:Colon / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D007583:Jejunum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics
D001647:Bile Acids and Salts; D002793:Cholic Acids; C004821:muricholic acid; D014580:Ursodeoxycholic Acid