CARRIER-MEDIATED TRANSPORT OF XENOBIOTICS IN LIVER CELLS

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Previous studies have demonstrated that the liver possesses a variety of active, carrier-mediated transport systems which are responsible for the hepatic uptake and elimination of a variety of foreign chemicals (xenobiotics) as well as endogenous compounds (steroids amino acids and bile acids). The long-term objectives of this proposal are to characterize the structural specificities, and the nature and significance of chemical modification of these transport systems. Specific aims of this proposal are to: 1) determine if transport of ouabain and/or procaine amide ethobromide (PAEB), prototype substrates for "neutral" and "organic cation" transport systems, respectively, is related to the transport of endogenous substances such as inorganic cations, amino acids or hexoses, 2) characterize the hepatocellular efflux processes for ouabain and PAEB, 3) define the relationship between the hepatocyte carrier-mediated transport system for ouabain and those for bile acids, 4) determine if such transport systems are functional in species other than the laboratory rat, 5) determine if such transport systems can be induced by prior exposure to transport-system substrates and 6) further examine the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on these transport systems in isolated hepatocytes. Isolated hepatic parenchymal cells in suspension are utilized to examine the rate of accumulation and efflux of radiolabeled ouabain, taurocholic acid and PAEB, each of which is transported by different carrier-systems. Kinetic analysis of the initial rates of uptake of various concentrations of these substrates in the presence of other potential substrates, or from isolated hepatocytes obtained from TCDD-treated animals, should provide information on the structural specificities and redundancies of these carrier-mediated transport systems. Preparation of isolated hepatocytes from trout, mice, guinea pig and macaque should provide information on the phylogenetic preservation of these transport systems, and an evaluation of their significance in species other than the rat. Results of these studies will be of significance in 1) defining potential rate-limiting steps for the hepatic elimination of various drugs and toxicants, and 2) understanding and/or predicting potential chemical interactions that might occur through competitive interaction or chemical modification of these hepatic transport systems upon exposure to various drugs and/or environmental hepatotoxic chemicals.