It is widely accepted that the hepatotoxicity of CCl4 results from the metabolism of CCl4 to the trichloromethyl free radical by cytochrome P- 450. Earlier studies reported that sublethally CCl4-treated rabbits were 1`0 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-alpha, leukotrienes, and nitric oxide (NO), thereby causing cellular damage. Upon CCl4 administration, Kupffer cells increase in number and peripheral monocytes/ macrophages are recruited to the liver. Both Kupffer cells and hepatocytes respond to cytokines and endotoxin by expressing an inducible isoform of nitric oxide synthase (NOS). We published data showing that, upon immunologic activation with endotoxin, NO was produced synergistically in whole blood and livers of rats that had been treated previously with CCl4. Nitrosyl complexes formed by NO binding to the hemoproteins, hemoglobin (whole blood) and cytochrome P-450 (liver biopsies) were measured with EPR spectroscopy. Decreased nitrosyl hemoprotein complex formation occurred in livers following treatment with either an inhibitor of macrophage activation (GdCl3), an inhibitor of cytokine responses (dexamethasone), or a ~NO synthase inhibitor (N-monomethyl-L-arginine, L-NMA). GdCl3 or dexamethasone treatment decreased TNF-alpha levels, while L-NMA treatment increased them. TNF-alpha levels, but not nitric oxide hemoprotein complex concentrations, correlated with increased hepatic damage as indicated by release of hepatic enzymes into the serum. In fact, the L- NMA NOS inhibitor actually increased hepatic damage. It appears that NO may play a protective role, and TNF-alpha, which is found at high concentrations, may be associated with pathophysiological responses.
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