Acquired forms of cholestatic liver disease such as primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis, and cholestasis of pregnancy result in a substantial clinical burden. Additionally, cholestasis secondary to sepsis is an essential component of multiple organ dysfunction syndrome which is the leading cause of death in critically ill patients. Clinically, a common treatment regimen for cholestasis includes the administration of phenobarbital which does not relieve cholestasis or any of its various causes, but rather is used to reduce the appearance of side effects such as hepatotoxicity. It is likely that the induction of drug transporters by phenobarbital as a compensatory transport and excretion pathway is the mechanism for this clinical observation. We are investigating alternative means to activate this molecular defense mechanism which may represent an important advance in the clinical management of cholestasis.

Regulation of the processes by which chemicals exit the cell during chemical exposure and cholestasis, especially metabolites produced by Phase I and Phase II biotransformation is not well understood. Understanding of the mechanisms that control drug transporter-mediated excretion of organic anions can potentially serve the scientific and medical community in our objective to create safe and biologically active drugs that alleviate specific transport deficiencies or up-regulate the excretion of chemicals in patients or exposed individuals.