Document Detail


Competition in liver transport between chenodeoxycholic acid and ursodeoxycholic acid as a mechanism for ursodeoxycholic acid and its amidates' protection of liver damage induced by chenodeoxycholic acid.
MedLine Citation:
PMID:  11515630     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Ursodeoxycholic acid has been widely used as a therapeutic agent in cholesterol gallstones and liver disease patients, but its mechanism of action is still under investigation. AIMS: The protective effect of ursodeoxycholic acid, both free, taurine and glycine conjugated, against hepatotoxic bile acids such as chenodeoxycholic acid and its taurine amidate was studied in bile fistula rats and compared with the cholic and taurocholic acid effect. METHODS: Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid, taurocholic acid and cholic acid were infused iv over 1 hour (8 micromol/min/kg) together with an equimolar dose of either taurochenodeoxycholic acid or chenodeoxycholc acid. Bile flow, total and individual bile acid and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. RESULTS: Taurochenodeoxycholic acid and chenodeoxycholc acid caused cholestasis and liver damage associated with a decreased bile flow, total and individual bile acids secretion accompanied by a biliary leakage of lactate dehydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxycholic acid and taurocholic acid, on the contrary, were choleretic, inducing an opposite effect on biliary parameters. Simultaneous infusion of taurochenodeoxycholic acid and the protective bile acid resulted in a functional and morphological improvement of the above parameters in the following order: glycine ursodeoxycholic acid > tauroursodeoxycholic acid > ursodeoxycholic acid followed by taurocholic acid; cholic acid was ineffective. CONCLUSIONS: The results show the protective effect of glycine ursodeoxycholic acid, ursodeoxycholic acid and tauroursodeoxycholic acid. This may be due to a facilitated transport of the toxic bile acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protective effect of ursodeoxycholic acid and its amidates with respect to cholic acid and its taurine conjugated form seems to be related to their different lipophilicity and micellar forming capacity.
Authors:
F Piazza; M Montagnani; C Russo; F Azzaroli; R Aldini; E Roda; A Roda
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver     Volume:  32     ISSN:  1590-8658     ISO Abbreviation:  Dig Liver Dis     Publication Date:  2000 May 
Date Detail:
Created Date:  2001-08-22     Completed Date:  2001-09-06     Revised Date:  2004-12-03    
Medline Journal Info:
Nlm Unique ID:  100958385     Medline TA:  Dig Liver Dis     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  318-28     Citation Subset:  IM    
Affiliation:
Department of Pharmaceutical Sciences, University of Bologna, Italy.
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MeSH Terms
Descriptor/Qualifier:
Alkaline Phosphatase / metabolism
Animals
Bile Acids and Salts / metabolism
Carrier Proteins / physiology
Chenodeoxycholic Acid / pharmacokinetics*,  pharmacology
Humans
Hydroxysteroid Dehydrogenases*
L-Lactate Dehydrogenase / metabolism
Liver / drug effects*,  physiology
Liver Diseases / drug therapy
Male
Membrane Glycoproteins*
Rats
Rats, Sprague-Dawley
Taurochenodeoxycholic Acid / pharmacokinetics*,  pharmacology
Ursodeoxycholic Acid / analogs & derivatives,  pharmacokinetics*,  pharmacology
Chemical
Reg. No./Substance:
0/Bile Acids and Salts; 0/Carrier Proteins; 0/Membrane Glycoproteins; 0/bile acid binding proteins; 128-13-2/Ursodeoxycholic Acid; 14605-22-2/tauroursodeoxycholic acid; 474-25-9/Chenodeoxycholic Acid; 516-35-8/Taurochenodeoxycholic Acid; 64480-66-6/glycoursodeoxycholic acid; EC 1.1.-/Hydroxysteroid Dehydrogenases; EC 1.1.1.-/AKR1C2 protein, human; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 3.1.3.1/Alkaline Phosphatase

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