It is widely accepted that the hepatotoxicity of CCl4 results from the metabolism of CCl4 to the trichloromethyl free radical by cytochrome P-450. This free radical and related reactive species cause cellular damage by initiating lipid peroxidation and covalently binding to protein, ultimately leading to cell death. Earlier studies reported that sublethally CCl4-treated rabbits were 120 times more susceptible than normal rabbits to the lethal effect of bacterial endotoxin. Endotoxin absorbed from the gut becomes involved in hepatotoxicity by its interaction with peritoneal and splenic macrophages and Kupffer cells. These cells, when stimulated, produce reactive mediators, including oxygen-derived free radicals, tumor necrosis factor- (TNF- ), leukotrienes, and nitric oxide ( NO), thereby causing cellular damage. Therefore it is plausible that NO plays an important role during hepatic necrosis caused by toxicants. In vivo NO production and its role in experimental animals exposed to hepatotoxicants had not been demonstrated before this work. NO is detected in vivo as ferrous hemoproteins nitrosyl complexes, P450-NO, HbNO, etc. and as iron-sulfur dinitrosyl complexes of unknown origin. NO complexation inhibits P450 and NO stimulates guanylate cyclase, but in general is not thoought to lead to irreversible damage. In contrast, protein nitrotyrosine formation content has become a frequently used technique for the detection of irreversible NO-dependent oxidative tissue damage. Formation of nitrotyrosine is usually interpreted as proof of in vivo peroxynitrite formation. We have discovered a tyrosyl radical-dependent, peroxynitrite-independent route to nitrotyrosine formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES050141-04
Application #
6106716
Study Section
Special Emphasis Panel (LPC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Rusyn, I; Kadiiska, M B; Dikalova, A et al. (2001) Phthalates rapidly increase production of reactive oxygen species in vivo: role of Kupffer cells. Mol Pharmacol 59:744-50
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Kono, H; Nakagami, M; Rusyn, I et al. (2001) Development of an animal model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol 280:G1178-86
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Hix, S; Kadiiska, M B; Mason, R P et al. (2000) In vivo metabolism of tert-butyl hydroperoxide to methyl radicals. EPR spin-trapping and DNA methylation studies. Chem Res Toxicol 13:1056-64
Nakao, L S; Kadiiska, M B; Mason, R P et al. (2000) Metabolism of acetaldehyde to methyl and acetyl radicals: in vitro and in vivo electron paramagnetic resonance spin-trapping studies. Free Radic Biol Med 29:721-9

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