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 agen t in cholesterol gallstones and liver disease patients, but its mechanism o f action is still under investigation. Aims. The protective effect of ursodeoxycholic acid, both free, taurine and glycine conjugated, against hepatotoxic bile acids such as chenodeoxycholi c acid and its taurine amidate was studied in bile fistula rats and compare d with the cholic and taurocholic acid effect. Methods. Tauroursodeoxycholic acid, glycine ursodeoxycholic acid, ursodeoxy cholic acid, taurocholic acid and cholic acid were infused iv over 1 hour ( 8 mu mol/min/kg) together with an equimolar dose of either taurochenodeoxyc holic acid or chenodeoxycholc acid. Bile flow; total and individual bile ac id and biliary lactate dehydrogenase and alkaline phosphatase enzymes were measured. Results. Taurochenodeoxycholic acid and chenodeoxycholc acid caused cholest asis and liver damage associated with a decreased bile flow, total and indi vidual bile acids secretion accompanied by a biliary leakage of lactate deh ydrogenase and alkaline phosphatase enzymes. Tauroursodeoxycholic acid, gly cine ursodeoxycholic acid, ursodeoxycholic acid and taurocholic acid, on th e contrary, were choleretic, inducing an opposite effect on biliary paramet ers. Simultaneous infusion of taurochenodeoxycholic acid and the protective bile acid resulted in a functional and morphological improvement of the ab ove parameters in the following order: glycine ursodeoxycholic acid > tauro ursodeoxycholic acid > ursodeoxycholic acid followed by taurocholic acid; c holic acid was ineffective. Conclusions. The results show the protective effect of glycine ursodeoxycho lic acid, ursodeoxycholic acid and tauroursodeoxycholic acid. This may be d ue to a facilitated transport of the toxic bile acid into bile; conjugation with taurine is less effective than glycine. Finally, the better protectiv e effect of ursodeoxycholic acid and its amidates with respect to cholic ac id and its taurine conjugated form seems to be related to their different l ipophilicity and micellar forming capacity.