REGULATION OF HEPATIC UPTAKE OF DRUGS AND XENOBIOTICS

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DESCRIPTION (Verbatim from Applicant's Abstract): Cellular uptake of xenobiotics is a fundamental phenomenon required for endogenous biochemicals, pharmaceuticals, and chemicals to elicit any number of biochemical, pharmacological, and/or toxicological events within the cell. It seems intuitive that the mechanism(s) by which xenobiotics are transported into hepatic parenchymal cells will affect the rate at which hepatocellular biotransformation and biliary excretion occur. Transport mechanisms are putatively responsible for the hepatic uptake of organic molecules. The organic anion transporting polypeptides, oatp1 and oatp2, mediate sodium-independent transport of a broad range of organic anions (e.g., bile acids, estrogen conjugates, leukotriene conjugates, unconjugated bilirubin, and cardiac glycosides) into hepatocytes. The oatp1 and oatp2 sinusoidal transporters constitute an important transport system that we postulate to be regulated by both age and microsomal enzyme inducing chemicals. The studies proposed are designed to: (1) determine the constitutive expression levels of oatp1 and oatp2 in liver of adult rats, and determine whether the expression is inducible by microsomal enzyme inducers; (2) determine whether the increased expression of oatp1 and oatp2 in adult rats by microsomal enzyme inducers is related to an increase in plasma disappearance and hepatic uptake of xenobiotics; and (3) determine whether the expression of oatp1 and oatp2 is detectable in liver of newborn rats, and whether the expression progressively increases in a temporal fashion in young animals. We will also determine whether the expression of oatp1 and oatp2 in young animals can be induced to adult levels by classical microsomal enzyme inducers; (4) determine whether the expression of oatp1 and oatp2 in newborn and young rats is related to plasma disappearance and hepatic uptake of xenobiotics; (5) determine whether the transcriptional upregulation of oatp genes requires the involvement of the recently reported pregnane-X-receptor (PXR)-response element that affords transcriptional inducibility of many genes by pregnenolone-16alpha-carbonitrile (PCN); and (6) determine whether the induction of oatps by PCN-type inducers involves the PXR. Overall, these studies will determine the significance of oatp1 and oatp2 in hepatocellular uptake.