The liver is strategically located between the gut and the systemic circulation. Consequently, substances absorbed in the intestine have to pass the liver, before they reach the systemic circulation putting the liver as a second barrier after the intestinal wall for preventing the entry of potentially harmful substances from the intestine into the body. Consequently, the liver is a central organ in drug disposition, in particular if they are amphipathic or hydrophobic. Hence, understanding the uptake of drugs into hepatocytes, the main cell type in liver, and the export of drug metabolites from hepatocytes is essential for developing models of drug disposition as well as for predict potential harmful effects of drugs and/or their metabolites on the liver.
Using bile salts as model molecules, the team of the Division of Clinical Pharmacology and Toxicology of the University Hospital Zurich started in the late 1980th the cloning of bile salt transporters using for SLC family members the expression cloning methodology developed by M. Hediger. The team succeeded in cloning the key uptake systems for bile salts, which are the founding members of the SLC10A and the SLCO families. Cloning of the major if not exclusive export system for bile salts identified it as a member of the ABC-transporter superfamily. The SLCO transporter family was subsequently established as a major drug transporter family by us and individual members were identified in many organs.
Based on this work, Stieger and the team worked out the mechanism for drug induced cholestasis by demonstrating the interference of such drugs with the process of canalicular bile salt secretion.
Function in NCCR
- Principal Investigator (PI)
Senior Research Associate, Division of Clinical Pharmacology and Toxicology, University Hospital Zurich
- Ph.D. in Biochemistry at the Swiss Federal Institute of Technology, Zurich
- M.Sc. in Biochemistry at the Swiss Federal Institute of Technology, Zurich
- American Physiological Society
- American Society of Cell Biology
- Swiss Society of Biochemistry
- Swiss Association for the Study of Liver Disease