|RONIS, MARTIN - Arkansas Children'S Nutrition Research Center (ACNC)|
|KOROURIAN, SOHEILA - University Arkansas For Medical Sciences (UAMS)|
|BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC)|
|BADEAUX, JAMIE - Arkansas Children'S Nutrition Research Center (ACNC)|
|BADGER, THOMAS - Arkansas Children'S Nutrition Research Center (ACNC)|
Submitted to: Alcohol
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/5/2009
Publication Date: 3/1/2010
Citation: Ronis, M.J., Korourian, S., Blackburn, M., Badeaux, J., Badger, T.M. 2010. The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat. Alcohol. 44(2):157-169.
Interpretive Summary: Alcohol is a significant component of the diet of many Americans. Excessive alcohol consumption causes tissue damage; whereas, consumption of low levels of alcohol can have beneficial health effects. This study identified the relative importance of two enzymes that metabolize alcohol in the alcohol-induced cell damage. Our results suggest that a significant amount of liver injury after drinking alcohol is produced by: 1) ethanol itself; 2) alcohol metabolism by one enzyme (CYP2E1), which is linked in part to buildup of fat in the liver and to inflammation; and 2) alcohol metabolism by another enzyme (ADH) which is linked in part to liver stress and cell death.
Technical Abstract: The importance of ethanol metabolism in the development of alcoholic liver disease remains controversial. The present study examined the effects of selective inhibition of the cytochrome P450 enzyme CYP2E1, compared with the inhibition of overall ethanol metabolism on the development of alcoholic steatohepatitis. Adult male Sprague–Dawley rats were fed via total enteral nutrition for 45 days with or without 10–12 g/kg/d ethanol. Some groups were given 200 mg/kg/d of the CYP2E1 inhibitor diallyl sulfide (DAS). Other groups were treated with 164 mg/kg/d of the alcohol dehydrogenase (ADH) inhibitor 4-methylpyrazole (4-MP), and dosed at 2–3 g/kg/d ethanol to maintain similar average urine ethanol concentrations. Liver pathology scores and levels of apoptosis were elevated by ethanol (P < .05), but did not differ significantly on co treatment with DAS or 4-MP. However, liver triglycerides were lower when ethanol-fed rats were treated with DAS or 4-MP (P < .05). Serum alanine aminotransferase values were significantly lower in ethanol-fed 4-MP–treated rats indicating reduced necrosis. Hepatic oxidative stress and the endoplasmic reticulum (ER) stress marker tribbles-related protein 3 were increased after ethanol (P < .05); further increased by DAS, but partly attenuated by 4-MP. Both DAS and 4-MP reversed ethanol increases in the cytokine, tumor necrosis factor-alpha (TNF-alpha), and the chemokine CXCL-2 (P < .05). However, neither inhibitor prevented ethanol suppression of interleukins IL-4 or IL-12. Moreover, neither inhibitor prevented ethanol increases in tumor growth factor-beta mRNA. Ethanol and DAS additively induced hepatic hyperplasia (P < .05). These data suggest that a significant proportion of hepatic injury after ethanol exposure is independent of alcohol metabolism. Ethanol metabolism by CYP2E1 may be linked in part to triglyceride accumulation, to induction of TNF-alpha, and to chemokine production. Ethanol metabolism by ADH may be linked in part to oxidative and ER stress and necrotic injury.