Rats fed a high-fat ethanol-containing diet for 2 weeks were found to generate free radicals in liver and heart in vivo. The radicals are believed to be carbon-centered radicals, were detected by administering spin-trapping agents to the rats, and were characterized by electron paramagnetic resonance spectroscopy. The radicals in the liver were demonstrated to be localized in the endoplasmic reticulum. Rats fed ethanol in a low-fat diet showed significantly less free radical generation. Control animals given isocaloric diets without ethanol showed no evidence of free radicals in liver and heart. When liver microsomes prepared from rats fed the high-fat ethanol diet were incubated in a system containing ethanol, NADPH, and a spin-trapping agent, the generation of 1-hydroxyethyl radicals was observed. The latter was verified by using "3C-substituted ethanol. Microsomes from animals fed the high-fat ethanol-containing diet had higher levels of cytochrome P-450 than microsomes from rats fed the low-fat ethanol-containing diet. The results suggest that the consumption of ethanol results in the production of free radicals in rat liver and heart in vivo that appear to initiate lipid peroxidation.Chronic excessive use of alcohol by humans results in liver disease (1, 2) characterized by fatty infiltration, which can lead to fibrotic degeneration and necrosis (1,3,4). However, the mechanisms leading to the development of alcoholic liver disease remain unclear. Lipid peroxidation was linked to ethanol consumption by Di Luzio and coworkers (5, 6), who reported that antioxidants prevented the development of fatty liver after a large acute dose of ethanol. Investigations by others have subsequently indicated that lipid peroxidation appears to occur in the livers of animals soon after the administration of an acute dose of alcohol. Much of the evidence for these claims has been based on the thiobarbituric acid assay for malondialdehyde in livers of animals treated with ethanol (7, 8), but increases in conjugated dienes and chemiluminescence as well as decreases in hepatic glutathione have also been reported (8). In addition, Muller and Sies (9) have reported an enhanced production of ethane and n-pentane, which are believed to be products of the peroxidative degradation of membrane lipids, during the metabolism of ethanol by perfused livers. These various findings have been interpreted as evidence that lipid peroxidation has occurred in the liver as a result of ethanol metabolism. Lipid peroxidation has also been proposed as a mechanism of ethanol-induced toxicity in the heart (10), gastric mucosa (11), and testes (12). However, the role of peroxidative events in the development of human alcoholrelated disease is highly controversial.Mechanisms that may initiate lipid peroxidation after ethanol exposure are also uncertain. Several laboratories have presented evidence that chronic ethanol feeding stimulates the production of hydroxyl radicals by liver microsomes (13,14). If this type of radical production occurs in the...

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1. In streptozotocin-induced diabetic male rats, hepatic microsomal aminopyrine N-demethylase activity was depressed, whereas aniline hydroxylase activity and cytochrome P-450 content were increased over control values. 2. In diabetic female rats, hepatic microsomal aminopyrine N-demethylase activity, aniline hydroxylase activity, biphenyl 4-hydroxylase activity, and cytochrome P-450 content were increased over control values. 3. Insulin treatment of diabetic male and female rats antagonized all physical and biochemical abnormalities of the diabetic state; 4. Methyl analogues of streptozotocin did not produce a diabetic state when injected into female rats, and resulted in no changes in aminopyrine N-demethylase activity, aniline hydroxylase activity, or cytochrome P-450 content. 5. Insulin treatment of non-diabetic female rats resulted in slight decreases in aminopyrine N-demethylase and aniline hydroxylase activities, but no changes in cytochrome P-450 content. These observations suggest that insulin primarily influences drug metabolism of diabetic animals through correction of the insulin-deficient diabetic state.

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