We plan to continue with our studies on the relative importance of the covalent binding of carbon tetrachloride reactive metabolites and lipid peroxidation in carbon tetrachloride-induced liver injury. We also plan to continue with studies directed to understand how cellular alterations initiated by carbon tetrachloride at the cytochrome P-450 site in the endoplasmic reticulum propagate to other cell organelles like the Golgi apparatus, plasma membrane, and the cytoplasm. We plan to perform studies directed to understand the mechanism by which disruption of calcium homeostasis during carbon tetrachloride poisoning initiates the chain of events ending in liver cell necrosis. We plan to further explore the possible role of processes of synthesis and degradation of cellular constituents in carbon tetrachloride-induced liver necrosis. Particular emphasis in protein and phospholipid degradation is going to be made. A major area of research effort in our project, is going to be the development of treatment/antidotes preventing liver cell necrosis, based on our studies on the mechanism of carbon tetrachloride-induced liver injury. We plan to explore the possibility that insights gained from the studies on cell injury by the model hepatotoxin carbon tetrachloride allowed prevention of liver cell necrosis by other hepatotoxins and cell necrosis produced by other chemicals acting in other organs like pancreas, small intestine, kidney or testes. Health implications of this project are critical, since the aim of our research is to understand how cells die after chemical or other insult and how that understanding can be used to develop treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK013195-18
Application #
3224978
Study Section
Toxicology Study Section (TOX)
Project Start
1979-01-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1990-06-30
Support Year
18
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Naval Institute of Sci & Tech Research
Department
Type
DUNS #
City
Buenos Aires
State
Country
Argentina
Zip Code
de Mecca, M M; Castro, G D; Diaz Gomez, M I et al. (1995) Dithiothreitol inhibitory effects on carbon tetrachloride-promoted NADPH-dependent lipid peroxidation in liver microsomal suspensions. Res Commun Mol Pathol Pharmacol 88:205-13
de Ferreyra, E C; Bernacchi, A S; San Martin, M F et al. (1995) Late protective effects of the anticalmodulin drug fluphenazine on carbon tetrachloride-induced liver necrosis. Biomed Environ Sci 8:218-25
de Ferreyra, E C; Bernacchi, A S; San Martin, M F et al. (1995) Trifluopromazine late preventive effects on carbon tetrachloride-induced liver necrosis. Exp Mol Pathol 62:75-82
Valles, E G; de Castro, C R; Castro, J A (1994) N-acetyl cysteine is an early but also a late preventive agent against carbon tetrachloride-induced liver necrosis. Toxicol Lett 71:87-95
de Toranzo, E G; Castro, J A (1994) Reaction of 4-hydroxynonenal with some thiol-containing radioprotective agents or their active metabolites. Free Radic Biol Med 17:605-7
de Ferreyra, E C; Bernacchi, A S; San Martin, M F et al. (1994) Nicotinamide late protective effects against carbon tetrachloride-induced liver necrosis. Exp Mol Pathol 60:214-23
de Ferreyra, E C; Bernacchi, A S; Villarruel, M C et al. (1993) Prevention of CCl4-induced liver necrosis by the calcium chelator arsenazo III. Exp Mol Pathol 58:194-204
de Mecca, M M; Castro, G D; Castro, J A (1993) Antioxidative stress therapy with dithiothreitol tetraacetate. I. Protection against carbon tetrachloride induced liver necrosis. Arch Toxicol 67:547-51
de Mecca, M M; Castro, G D; Castro, J A (1993) Dithiothreitol tetraacetate S-acetyl esterase activity in blood and in different tissues of male rats. Arch Int Pharmacodyn Ther 326:101-8
Gonzalez Padron, A; de Toranzo, E G; Castro, J A (1993) Late preventive effects of quinacrine on carbon tetrachloride induced liver necrosis. Arch Toxicol 67:386-91

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