Regulation of Hepatic Uptake of Drugs and Xenobiotics

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DESCRIPTION (provided by applicant): Cellular uptake is a fundamental phenomenon required for endogenous compounds and xenobiotics, such as drugs and environmental pollutants, to elicit physiological, pharmacological, and toxicological events within the cell. One might expect that the mechanism(s) by which xenobiotics are transported into hepatic parenchymal cells will affect hepatocellular biotransformation and biliary excretion. There are numerous transport mechanisms putatively responsible for hepatic sinusoidal uptake of organic molecules. These mechanisms include sodium-independent transport of a broad range of organic anions mediated by organic anion transporting polypeptides (Oatps). The Oatp sinusoidal transporters constitute an important organic anion transport system that we postulate will be regulated by classical enzyme inducing chemicals and bile acids. Despite much progress made in cloning and identifying Oatps, there is only a limited understanding of the regulation and function of Oatps. This deficiency, coupled with the emergence of the mouse genome sequence and the availability of numerous knockout mouse models, provides us an unprecedented opportunity to study and understand the regulation of Oatp gene expression. In parallel, our newly developed Oatp4-null mouse (the first and only Oatp-null mouse) gives our laboratory a unique tool to examine functions of this important Oatp in vivo. Therefore, the current proposal represents our plans to: (1) determine the molecular regulatory mechanisms responsible for both constitutive and altered expression of the Oatp gene family in liver, and (2) characterize the in vivo function of the liver-specific transporter Oatp4. The data generated regarding the expression and regulation of Oatps, as well as functional data from our Oatp4-null mouse will greatly advance our knowledge concerning the importance of Oatps in physiology, pharmacology, and toxicology, and ultimately not only aid the scientific community in predicting drug efficacy and safety in humans, but allow the development of liver-specific drug delivery.