Hepatic clearance and biliary excretion of a variety of organic and inorganic ions are decreased in many fetal and suckling mammals compared with the adult. Immaturity of hepatic transport may result in dangerous accumulation of some drugs in plasma, retention of endogenous toxins such as bilirubin and bile acids, and possibly an increased susceptibility to cholestatic liver disease. The current proposal will test the hypothesis that determinants of hepatic ion transport including the sodium pump (Na+, K+, ATPase), ion exchangers, the transmembrane potential, and specific membrane carriers on the basolateral and canalicular membranes develop asynchronously during fetal and postnatal life to meet the liver's requirements first for rapid growth and only later for more specialized activities such as bile formation. The activity of Na+,K+ ATPse, which provides the driving force for transport of many substrates, will be determined in fetal and neonatal basolateral plasma membranes and compared to adult membranes. The development of bile acid transport will be characterized in basolateral and canalicular plasma membrane vesicles; the ontogeny of hepatic bile acid transport will be compared to that for Na+ coupled amino acid (taurine and alanine) transport. The role of Na+-independent mechanisms for transport across the basolateral membrane such as -OH/anion exchange will be examined in membrane vesicles from developing liver. The effects of age and species (rat), specific albumin on bile acid uptake will also be studied in basolateral membranes vesicles. The development of the Na+/H+ antiporter on the basolateral membrane and a Cl-/HCO3- exchanger on the apical membrane will be examined in membrane vesicles. Both transporters contribute to biliary bicarbonate excretion and may drive other anion exchangers involved in bile formation. Growth associated-alternations in the transmembrane potential (Em), which would influence net ion flux in and out of the hepatocyte, will be measured in neonatal liver using microelectrodes. The contributions of Na+,K+ ATPase and membrane permeability to the Em will be defined. A possible role for epidermal growth factor (EGF) in the modulation of perinatal hepatic transport will be considered including the effects of injected EGF on neonatal Na+/H+ exchange and Na+ coupled carriers and the effects of EGF-mediated phosphorylation of the plasma membrane on regulation of transport.
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