Hepatocytes free radical generation

The effects of chromium(III) chloride and sodium chromate(VI) on the hepatotoxicity of carbon tetrachloride exposure to mouse hepatocytes were examined by Tezuka et al. (1995). Primary cultures of mouse hepatocytes were pretreated with 10 or 100 pM chromium for 24 hours followed by exposure to 1-5 mM carbon tetrachloride for up to 1 hour. Chromium(VI) pretreatment significantly reduced the cell toxicity as well as lipid peroxidation caused by carbon tetrachloride. Chromium(III) pretreatment did not have any effect on cell toxicity. About 50% of chromium(VI) was taken up and reduced in the cells by 90% to chromium(III) within 10 minutes. The initial uptake rate of chromium(HI) into cells was greater than 500-fold less than chromium(VI), and only about 5% was absorbed. The protection against carbon tetrachloride damage by chromium(VI) was attributed to its rapid uptake and conversion to chromium(III), and it was determined that chromium(III) acts as a radical scavenger for the free radicals generated by carbon tetrachloride within the cell. Furthermore, chromium(VI) pretreatment reduced the activity of NADPH cytochrome c reductase which metabolizes carbon tetrachloride to reactive species. 

In contrast, acetaldehyde and free radicals generated from ethanol metabolism can result in alcohol-induced hepatitis, a condition in which the liver is inflamed and cells become necrotic and die. Diffuse damage to hepatocytes results in cirrhosis, characterized by fibrosis (scarring), disturbance of the normal architecture and blood flow, loss of liver function and, ultimately, hepatic failure. 

In mouse primary hepatocytes, treatment with 5 fiM usnic acid for 16 hours resulted in 98% cell death that appeared to be associated with cell necrosis rather than apoptosis. Results indicated that usnic acid was associated with inhibition and uncoupling of the electron transport chain in mitochondria. Usnic acid triggered oxidative stress by increasing free radical generation, and the oxidative stress appears to be critical in usnic acid-induced hepa-totoxicity (Han et al. 2004). 

Megamitochondria were induced in cultured rat hepatocytes by hydrazine and hydrogen peroxide, inducers of free radicals (Karbowski et al. 1997). Free radicals generated by different mechanisms or via different sources seem to be involved in their... 

Free radicals are generated from within hepatocytes in several ways, such as ionizing radiation, oxidative metabolism by cytochrome P450, reduction and oxidation (redox) reactions that occur during normal metabolism, transition... 

Several studies have shown that the reactive binding species generated by 1,1-dimethylhydrazine metabolism may be free radical intermediates. Rat liver microsomes and rat hepatocytes are capable of metabolizing 1,1-dimethylhydrazine to form methyl radical intermediates (Albano et al. 1989 Tomasi et al. 1987). The formation of tliese radicals was inhibited by the addition of inhibitors of cytochrome P-450 (SKF 525A, metyrapone, and carbon monoxide) and inhibitors of the flavin-containing monooxygenase system (methimazole). The formation of free radicals could also be supported nonenzymatically by the presence of copper ion (Tomasi et al. 1987). These data indicate that at least two independent enzyme systems and one nonenzymatic pathway may be involved in the metabolism of... 

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