Over the last few years, calcium has been emphasized as having a possible role in cell death produced by a number of toxic chemicals. Several studies now suggest that ionized calcium dramatically increases in hepatocytes exposed to a cytotoxic compound. This project will examine the role of this increase of ionized calcium in the cytoplasm produced by exposure of the cell to halogenated hydrocarbons (carbon tetrachloride, 1, 1- dichloroethylene, bromobenzene). Studies proposed will attempt to further validate primary cultures of hepatocytes as an appropriate model for these studies. Validation will be by examination of the role of metabolic activation of CC14 to chemically reactive intermediates and modification of activation by chemical alteration of the mixed function oxidase system. Studies with the model system will also characterize a discrepancy between the effects of CC14 on calcium homeostasis in vivo and in the tissue culture system. Another line of investigation will define a possible consequence of the increase of cytoplasmic calcium produced by halogenated hydrocarbon exposure. Activation of a calcium-sensitive endonuclease appears to play an important role in programmed cell death (apoptosis), and this will be examined in rat liver and monolayer cultures of hepatocytes after halogenated hydrocarbon exposure. Another major effort of the project will be to isolate and characterize mutant cell populations resistant to cytotoxicity produced by halogenated hydrocarbons. This effort will attempt to identify enzymatic systems critical in expression of cytotoxicity, or critical to protection of the cell from the cytotoxic effects of chemically reactive metabolites of the halogenated hydrocarbons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES003437-06
Application #
3250724
Study Section
Toxicology Study Section (TOX)
Project Start
1984-07-01
Project End
1992-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20852
Moore, L; Schoenberg, D R; Long, R M (1990) Impact of halogenated compounds on calcium homeostasis in hepatocytes. Environ Health Perspect 84:149-53
Long, R M; Moore, L; Schoenberg, D R (1989) Halocarbon hepatotoxicity is not initiated by Ca2+-stimulated endonuclease activation. Toxicol Appl Pharmacol 97:350-9
De Witt, L M; Jones, T W; Moore, L (1988) Stimulation of the renal endoplasmic reticulum calcium pump: a possible biomarker for platinate toxicity. Toxicol Appl Pharmacol 92:157-69
Long, R M; Moore, L (1988) Biochemical evaluation of rat hepatocyte primary cultures as a model for carbon tetrachloride hepatotoxicity: comparative studies in vivo and in vitro. Toxicol Appl Pharmacol 92:295-306
Long, R M; Moore, L (1988) Evaluation of the calcium mobilizing action of acetaminophen and bromobenzene in rat hepatocyte cultures. J Biochem Toxicol 3:353-62
Long, R M; Moore, L (1987) Cytosolic calcium after carbon tetrachloride, 1,1-dichloroethylene, and phenylephrine exposure. Studies in rat hepatocytes with phosphorylase a and quin2. Biochem Pharmacol 36:1215-21
Ray, P; Moore, L (1986) Carbon tetrachloride-induced release of calcium from isolated hepatocytes. Toxicology 41:205-12
Long, R M; Moore, L (1986) Inhibition of liver endoplasmic reticulum calcium pump by CCl4 and release of a sequestered calcium pool. Biochem Pharmacol 35:4131-7
Long, R M; Moore, L (1986) Elevated cytosolic calcium in rat hepatocytes exposed to carbon tetrachloride. J Pharmacol Exp Ther 238:186-91
Schanne, F A; Moore, L (1986) Liver plasma membrane calcium transport. Evidence for a Na+-dependent Ca2+ flux. J Biol Chem 261:9886-9