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.
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.


OBJECTIVE
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.
Piazza
F
F
Department of Pharmaceutical Sciences, University of Bologna, Italy.
Montagnani
M
M
Russo
C
C
Azzaroli
F
F
Aldini
R
R
Roda
E
E
Roda
A
A
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology; D002635:Chenodeoxycholic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008107:Liver Diseases / Q000188:drug therapy; D008297:Male; D008562:Membrane Glycoproteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013655:Taurochenodeoxycholic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000469:Alkaline Phosphatase; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002635:Chenodeoxycholic Acid; D006913:Hydroxysteroid Dehydrogenases; D007770:L-Lactate Dehydrogenase; D008562:Membrane Glycoproteins; D013655:Taurochenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; C037643:bile acid binding proteins; C031655:ursodoxicoltaurine; C024033:glycoursodeoxycholic acid; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)