The major goal of this research is to delineate mechanisms whereby environmental pollutants produce hepatotoxicity. The model compounds, carbon tetrachloride and allyl alcohol, selective toxins for pericentral and periportal regions of the liver, respectively, will be studied to gain understanding of why the metabolism of hepatotoxic chemicals and their influence on cellular events differ in periportal and pericentral regions of the liver lobule. Employing isolated, perfused rat and mouse liver, the following experiments are proposed to define the acute action of hepatotoxins: (1) Determine the effect of the two model toxins on mixed-function oxidation, conjugation, ethanol metabolism and oxygen tension in periportal and pericentral regions of the liver lobule employing a micro-light guide to detect fluorescent products or mini-electrodes to measure oxygen; (2) determine enzyme activities and key metabolites in periportal and pericentral zones by quantitative histochemistry; (3) examine tissue damage by light and electron microscopy. Throughout these studies, the nutritional state will be manipulated either by dietary means of the experimental animal or by the infusion of appropriate carbohydrates to the perfused liver. Methods will be developed to measure rates of CCl4, aflatoxin and allyl alcohol metabolism, glutathione-S-conjugation and to monitor Ca++ concentrations in periportal and pericentral regions of the liver lobule. In other studies, temporal changes in the above parameters following chronic, low-dose exposure of rats and mice to allyl alcohol and CCl4 will be investigated. To avoid the use of metabolic inhibitors, recombinant inbred lines of mice will be employed to establish causal relationships between biologic factors and hepatotoxicity. Knowledge gained in these studies will then be applied to other hepatotoxins including pesticides, vinyl chloride, styrene, benzene and toluene. Knowledge of metabolic factors involved in mechanisms of hepatotoxicity in intact cells may ultimately be applied to reducing the hazard of hepatotoxicity by environmental pollutants.
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