MRP1 and MRP2, founding members of the MRP family, are involved in cellular resistance to anticancer agents and drug disposition in the body. Studies in our laboratory and others now indicate that the MRP family extends to 9 members. In the previous funding period we focused on the analysis of the in vivo functions of MRP3 and MRP4, and on the elucidation of the functional properties of MRP6, MRP7 and MRP8. To accomplish this we developed and analyzed mrp3 and mrp4 knock-out mice and cell lines in which MRP6, MRP7 and MRP8 were ectopically expressed. Using our mrp3 knock-out mice, we showed that the Mrp3 functions in liver as a basolateral efflux pump for sulfate metabolites of xenobiotics, and that it similarly protects cholestatic liver from endogenous compounds such as bile acids. Our studies on Mrp4 knockout mice showed that Mrp4 is an in vivo resistance factor for the antiviral nucleotide analog PMEA, restricts penetration of this agent into brain, and like Mrp3, functions in the basolateral extrusion of sulfates from hepatocytes. MRP6, MRP7 and MRP8 were determined to be lipophilic anion transporters that are able to confer cellular resistance to anticancer natural product (MRP6, MRP7) and nucleoside-based agents (MRP8). In this application we propose to define the pharmacological functions of MRP4 as an in vivo resistance factor for anticancer agents, and as a component of the blood-brain and blood-cerebrospinal fluid barriers for anticancer agents. In addition, we will complete our investigation of the newly discovered MRP family members by determining the drug resistance abilities and substrate selectivity of MRP9 - the only MRP whose functional properties have not been determined to any extent. These studies will provide insights into factors that reduce the effectiveness of chemotherapeutic agents, as well as into medically relevant physiological processes in which these unusual pumps are involved.
The experiments in this proposal will promote public health by providing information on why many types of cancers are not successfully treated with anticancer agents. This information should assist in the development of agents and strategies that are more successful.
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