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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES002759-09
Application #
3250059
Study Section
Toxicology Subcommittee 2 (TOX)
Project Start
1981-12-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Przybocki, J M; Reuhl, K R; Thurman, R G et al. (1992) Involvement of nonparenchymal cells in oxygen-dependent hepatic injury by allyl alcohol. Toxicol Appl Pharmacol 115:57-63
Roochvarg, L B; Thurman, R G; Kauffman, F C (1992) 7-Ethoxycoumarin metabolism in hepatocytes from pre- and postpubescent male rats. Dev Pharmacol Ther 18:81-8
Lindert, K A; Caldwell-Kenkel, J C; Nukina, S et al. (1992) Activation of Kupffer cells on reperfusion following hypoxia: particle phagocytosis in a low-flow, reflow model. Am J Physiol 262:G345-50
Wall, K L; Gao, W; Qu, W et al. (1992) Food restriction increases detoxification of polycyclic aromatic hydrocarbons in the rat. Carcinogenesis 13:519-23
Yamanaka, H; Nukina, S; Handler, J A et al. (1992) Transient activation of hepatic glycogenolysis by thrombin in perfused rat livers. Eur J Biochem 208:753-9
Kauffman, F C; Whittaker, M; Anundi, I et al. (1991) Futile cycling of a sulfate conjugate by isolated hepatocytes. Mol Pharmacol 39:414-20
Ganey, P E; Thurman, R G (1991) Ethanol potentiates doxorubicin-induced inhibition of cell survival in cultured Chinese hamster ovary cells. Cancer Res 51:2036-40
te Koppele, J M; Keller, B J; Caldwell-Kenkel, J C et al. (1991) Effect of hepatotoxic chemicals and hypoxia on hepatic nonparenchymal cells: impairment of phagocytosis by Kupffer cells and disruption of the endothelium in rat livers perfused with colloidal carbon. Toxicol Appl Pharmacol 110:20-30
Marzi, I; Cowper, K; Takei, Y et al. (1991) Methyl palmitate prevents Kupffer cell activation and improves survival after orthotopic liver transplantation in the rat. Transpl Int 4:215-20
Ganey, P E; Keller, B; Lichtman, S N et al. (1991) A new method to monitor Kupffer cell phagocytosis continuously in perfused rat liver. Hepatology 13:567-74

Showing the most recent 10 out of 48 publications