It is known that hepatocytes undergoing active replication in response to mitogenic stimulation or during regeneration following chemical toxicity are resistant to the actions of hepatotoxic agents. However, the mechanism(s) for such resiliency remains unknown. Pilot studies from our laboratory demonstrate that hepatocytes induced to proliferate following the administration of sublethal doses of two model hepatotoxicants (acetaminophen and carbon tetrachloride) have elevated expression of the canalicular ATP-dependent efflux pump for organic anions known as MRP-2, alternatively known as canalicular MRP (cMRP) or c MOAT. We hypothesize that induction of hepatocellular proliferation results in an increased expression of this protein. The overall goal of the studies in this proposal is to better characterize the up-regulation of this transport protein, which could contribute to the resiliency of proliferating hepatoyctes to chemically, induced injury. Our first goal is to examine the temporal alterations in MRP-2 expression and its tissue distribution during hepatocellular regeneration. Then we will determine if induction of hepatocellular replication in vivo using other models of compensatory hyperplasia and direct mitogenesis similarly enhance the expression of MRP-2. The studies outlined in this AREA grant should provide the foundation for future studies intended to elucidate the functional consequences of changes in the expression of this protein in proliferating hepatocytes. We would like to put forward the notion that up-regulation of MRP-2 may be one of several mechanisms by which proliferating hepatocytes acquire resistance to chemical injury.
