Use of sandwich-cultured hepatocytes to evaluate impaired bile acid transport as a mechanism of drug-induced hepatotoxicity.

Drug-induced liver toxicity is a significant problem in drug development and clinical practice, yet its mechanisms are not well understood. Growing evidence suggests that inhibition of bile acid transport may be one mechanism of hepatotoxicity. A number of hepatic transporters work in concert to transport bile acids and xenobiotics from blood to bile, and many drugs have been shown to perturb this process with detrimental consequences. Hepatocytes cultured in a sandwich configuration maintain transporter activity and liver-specific metabolic functions; thus, the sandwich-cultured hepatocyte model represents a useful tool for evaluating hepatotoxicity caused by interference with hepatic transporters. As an example, the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone is one such drug that has been shown to inhibit bile acid transport in vitro. Data presented in this manuscript indicate that troglitazone inhibits both basolateral uptake and canalicular excretion of taurocholate in a concentration-dependent manner in both sandwich-cultured and suspended human and rat hepatocytes. These data confirm both the interaction of troglitazone with bile acid transporters in hepatocytes and the utility of the sandwich-cultured hepatocyte model to study such interactions.