Biotransformation and detoxication of xenobiotics, pharmaceuticals, and chemicals is intrinsically dependent on the organism's capacity to excrete these compounds. The excretory systems can be upregulated by chemotherapeutic agents in the phenomenon of multidrug resistance observed in many cancers. Chemotherapy-induced drug resistance is due to the overexpression of proteins which transport chemicals out of cancer cells. These proteins include P-glycoprotein and multidrug-resistance proteins (Mrp) which are encoded by the multiple drug resistance gene (MDR) and the mrp genes, respectively. In normal liver, localization of transport proteins in the canalicular membrane of hepatic parenchymal cells is physiologically important for export/excretion of chemicals into bile. One member of the mrp gene family, Mrp2 (formerly cMOAT), is an ATP-dependent canalicular transporter protein responsible for the excretion of various organic anions, including glutathione, sulfate, and glucuronide conjugates of chemicals and xenobiotics. These transport processes, of which Mrp2 is a critical component, are now considered the """"""""phase III"""""""" process of drug/chemical hepatic metabolism. The possibility that this third phase of biotransformation can be regulated in coordination with both phase I and II systems in response to chemical stimuli is intriguing and would suggest that all three phases of biotransformation are coupled to increase the efficiency of hepatocellular metabolism/detoxication of chemicals. This laboratory has reported on the ability of chemicals to increase hepatobiliary function, which we postulate to be intrinsically related to Mrp2 expression and function. The first two aims will test the hypothesis that these observations are due to altered phase III metabolism, more specifically altered Mrp2 regulation. This laboratory has published an extensive amount of research showing that marked increases in toxicity of chemicals in newborn animals occur as a result of chemical-induced enhanced hepatobiliary function.
Aim 3 of this application will test the hypothesis that chemical-elicited maturation of neonatal hepatobiliary function is due to enhancement of Mrp2 function and/or expression. Further, this laboratory has reported that chemical-chemical interactions can cause a transition shift in the vector of hepatic excretion to decrease hepatobiliary excretion and increase hepatovascular excretion.
Aim 4 will test the hypothesis that this transition in hepatic excretion occurs due to the chemical-induced differential expression of Mrp2 on the hepatobiliary membrane and Mrp3 on the sinusoidal membrane. The last Aim tests an entirely new concept in drug metabolism and control of proteins involved in biliary excretion, that is, that Mrp2 is regulated by an orphan nuclear receptor, the pregnane X receptor. Elucidation of mechanisms that control Mrp2-mediated excretion of drugs will continue to enlighten the scientific and medical communities as to the importance of xenobiotic transport processes in relation to creating safe and biologically active drugs that alleviate specific transport deficiencies and protecting the public from chemical exposure.
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