Study of human isoursodeoxycholic acid metabolism.
OBJECTIVE
The aim of this study was to examine the metabolism of isoursodeoxycholic acid (isoUDCA) in humans.


METHODS
IsoUDCA was synthesized of >99% purity and administered orally for 1 week, 3 x 250 mg/day, to six healthy male subjects. Bile acids were extracted from duodenal bile, serum, and 24-h urine samples collected before and at the end of the study period, separated into groups of conjugates, and analyzed by gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry.


RESULTS
IsoUDCA was tolerated without any side effect. Liver function tests did not change. Bile acid concentrations (mean+/-SEM) increased from 11.9+/-1.87 to 15.3+/-1.37 mmol/l in bile (n.s.), and from 3.4+/-0.10 to 6.8+/-0.43 micromol/l in serum (p<0.05). Urinary excretion of bile acids increased from 5.3+/-0.29 to 82.2+/-7.84 micromol/24 h (p<0.01). All changes were due to significant increases of isoUDCA and UDCA in bile, serum and urine, and of 3-dehydro-UDCA, the 3-oxo intermediate of isomerization, in bile and in serum. The relative enrichments of isoUDCA, UDCA, and 3-dehydro-UDCA, were: in bile, 2.2%, 25.7%, and 0.7%; in serum, 24.7%, 23.5%, and 6.1%; and in urine, 83.7%, 2.0%, and 2.4%. Whereas 78% of serum isoUDCA was unconjugated, 93-94% of biliary and urinary isoUDCA was conjugated with N-acetylglucosamine.


CONCLUSIONS
This study indicates good tolerance and significant intestinal absorption of orally administered isoUDCA. IsoUDCA is extensively isomerized, probably both by intestinal and hepatic enzymes to yield UDCA which became the major biliary compound. In vitro, using the human hepatoblastoma cell line Hep G2, isoUDCA was found to be cytoprotective towards ethanol-induced cell injuries.
Marschall
H U
HU
Department of Internal Medicine III, Aachen University of Technology, Germany.
Roeb
E
E
Yildiz
Y
Y
Busch
N
N
Nguyen
H
H
Purucker
E
E
Thomas
H G
HG
Matern
S
S
D000328:Adult; D001646:Bile / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014556:Urine / Q000737:chemistry; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000494:pharmacology
D000431:Ethanol; D014580:Ursodeoxycholic Acid; C106883:isoursodeoxycholic acid