Effect of thiazolidinediones on bile acid transport in rat liver.
The thiazolidinedione derivatives, troglitazone, rosiglitazone, and pioglitazone, are novel insulin-sensitizing drugs that are useful in the treatment of type 2 diabetes. However, hepatotoxicity associated with troglitazone led to its withdrawal from the market in March 2000. In view of case reports of hepatotoxicity from rosiglitazone and pioglitazone, it is unclear whether thiazolidinediones as a class are associated with hepatotoxicity. Although the mechanism of troglitazone-associated hepatotoxicity has not been elucidated, troglitazone and its major metabolite, troglitazone sulfate, competitively inhibit adenosine triphosphate (ATP)-dependent taurocholate transport in isolated rat canalicular liver plasma membrane vesicles mediated by the canalicular bile salt export pump (Bsep). These results suggest that cholestasis may be a factor in troglitazone-associated hepatotoxicity. To determine whether this effect is 1) limited to canalicular bile acid transport and 2) is specific to troglitazone, the effect of troglitazone, rosiglitazone, and ciglitazone on bile acid transport was examined in rat basolateral (blLPM) and canalicular (cLPM) liver plasma membrane vesicles. In cLPM vesicles, troglitazone, rosiglitazone, and ciglitazone (100 microM) all significantly inhibited ATP-dependent taurocholate transport. In blLPM vesicles, these three thiazolidinediones also significantly inhibited Na(+)-dependent taurocholate transport. Inhibition of bile acid transport was concentration dependent and competitive in both cLPM and blLPM vesicles. In conclusion, these findings are consistent with a class effect by thiazolidinediones on hepatic bile acid transport. If hepatotoxicity is associated with this effect, then hepatotoxicity is not limited to troglitazone. Alternatively, if hepatotoxicity is limited to troglitazone, other mechanisms are responsible for its reported hepatotoxicity.
Snow
Kris L
KL
Division of Gastroenterology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48105, USA.
Moseley
Richard H
RH
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000187:drug effects / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced / Q000503:physiopathology; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D022161:Transport Vesicles / Q000187:drug effects*; D000077288:Troglitazone
D001647:Bile Acids and Salts; D002839:Chromans; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077288:Troglitazone; C039671:ciglitazone