The objective of the proposed studies is to gain further insight into the mechanisms by which the liver removes various environmental chemicals and drugs from the blood and excretes them into the bile. The mechanism or mechanisms by which xenobiotics enter the liver will be examined by using the isolated hepatocyte technique. Further insight into the mechanisms which stimulate and regulate the development of hepatic excretory function will be examined by measuring hepatic uptake processes in rats of various ages and determining if substrates for the hepatic excretory mechanism will stimulate its development. The mechanisms responsible for the first-pass effect of xenobiotics will be examined and the importance of the first-pass effect on toxicity will be examined. Thus, by investigating the hepatic uptake and excretory mechanisms by a number of techniques, a deeper insight into the basic mechanisms of detoxification of foreign chemicals by biliary excretion will be gained, an area in which development has lagged relative to detoxification by metabolism and renal excretion.
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