The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

Feb 2, 2010Alcohol (Fayetteville, N.Y.)

How alcohol breakdown contributes to fatty liver disease with inflammation in rats

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Abstract

Ethanol-fed rats showed lower liver triglycerides when treated with inhibitors of ethanol metabolism.

Liver pathology scores and apoptosis levels increased with ethanol consumption but were not significantly affected by the CYP2E1 or ADH inhibitors.
Both diallyl sulfide (DAS) and 4-methylpyrazole (4-MP) treatment led to lower liver triglycerides in ethanol-fed rats.
Serum alanine aminotransferase levels were significantly lower in ethanol-fed rats treated with 4-MP, indicating reduced liver cell damage.
Ethanol exposure increased oxidative stress and the endoplasmic reticulum stress marker, but DAS further increased these effects while 4-MP mitigated them.
DAS and 4-MP reversed increases in the inflammatory cytokine TNF-alpha and chemokine CXCL-2 due to ethanol, but did not prevent other inflammatory changes.

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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 10-12g/kg/d ethanol. Some groups were given 200mg/kg/d of the CYP2E1 inhibitor diallyl sulfide (DAS). Other groups were treated with 164mg/kg/d of the alcohol dehydrogenase (ADH) inhibitor 4-methylpyrazole (4-MP) and dosed at 2-3g/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 cotreatment 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 inhibitors prevented ethanol suppression of interleukins IL-4 or IL-12. Moreover, neither inhibitors 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.

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The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

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