Molecular Regulation of Drug Transport Proteins
Research in my laboratory focuses on understanding the molecular mechanisms involved in regulation of drug transport proteins particularly as it pertains to pathophysiological changes in drug disposition. The influence of disease and endogenous mediators on the gene expression and functionality of transport proteins is examined using a combination of in vivo, in vitro, in situ and molecular biology techniques. The combination of these methods allows us to assess clinical relevance as well as to ascertain the underlying cellular and molecular mechanisms involved.
To date, studies in our laboratory have revealed that inflammatory responses, generated in many disease conditions, alter the expression and activity of the ABC drug efflux transporters in numerous tissues including the liver, kidney, intestine and blood brain barrier. This has the potential to alter the distribution and elimination of many clinically important drugs. Current studies are examining the regulation of drug transporters in the placenta. The placenta serves as a protective barrier for the fetus. Several ABC drug efflux transporters are highly expressed in the placenta and are believed to limit the passage of xenobiotics into the fetus; thereby altering fetal drug exposure. Many prevalent obstetric complications generate an inflammatory response and to date, virtually nothing is known about the impact of maternal disease on the regulation and activity of drug transporters. Therefore, our research group has begun to explore the influence of highly prevalent maternal complications on the ABC- drug transporters and predict how these changes may affect the placental transfer and fetal exposure of drugs used in pregnant women.
Another research direction of the laboratory has focused on examining methods to suppress the the ABC drug efflux transporters in tumor cells, a leading cause of multidrug resistance and drug failure in cancer. This has resulted in collaborative research programs with Dr. Christine Allen and Dr. Ray Reilly with the primary goal to develop novel therapeutics and treatment strategies in the treatment of ovarian and breast cancer.
Leslie Dan Faculty of Pharmacy
University of Toronto
144 College Street
Toronto, Ontario, M5S 3M2