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United States Department of Agriculture

Agricultural Research Service

Research Project: IMPACT OF EARLY DIETARY FACTORS ON CHILD DEVELOPMENT AND HEALTH

Location: Arkansas Children's Nutrition Center

Title: The role of ethanol metabolism in alcohol-induced hepatotoxicity

Authors
item Ronis, Martin -
item Ferguson, Matthew -
item Badeaux, Jamie -
item Blackburn, Michael -
item Korourian, S -
item Badger, Thomas -

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: December 5, 2008
Publication Date: March 1, 2009
Repository URL: http://https://www.toxicology.org/ai/pub/Toxicologist_archive.asp
Citation: Ronis, M.J., Ferguson, M.E., Badeaux, J., Blackburn, M.L., Korourian, S., Badger, T.M. 2009. The role of ethanol metabolism in alcohol-induced hepatotoxicity [abstract]. The Toxicologist. 108(1):237. Abstract No. 1140.

Technical Abstract: The role of ethanol (EtOH) metabolism in liver injury remains a topic of controversy. In the current study, groups of male Sprague-Dawley rats (n = 4-8) were infused with 12 g/kg/d EtOH as part of isocaloric liquid diets fed via total enteral nutrition for 45 d. Some groups were given 200 mg/kg/d diallylsulfide (DAS) in the diet, which prevented induction of CYP2E1 apoprotein or activity after EtOH treatment. Other groups were infused diets supplemented with 164 mg/kg/d of the alcohol dehydrogenase inhibitor 4-methylpyazole (4MP) and dosed at 2-3 g/kg/d EtOH to maintain average blood ethanol concentrations in the 200-400 mg/dL range. Resulting liver pathology scores and levels of apoptosis did not differ significantly between EtOH, EtOH + DAS, or EtOH + 4MP groups, although serum ALT values were lower after 4MP treatment (p < 0.05). Hepatic oxidative stress measures (lipid peroxidation, (TBARS) and reduction in GSH concentrations) were increased after EtOH (p < 0.05), but unaffected by DAS or 4MP. DAS and 4MP blocked EtOH increases in TNF' mRNA (p < 0.05), and 4MP prevented EtOH increases in expression of the chemokine CXCL-2 (p < 0.05). However, neither inhibitor prevented EtOH suppression of IL-4 or IL-12 mRNAs or increases in TGF' mRNA (p < 0.05). The ER stress marker TRB3 was elevated by EtOH (p < 0.05), and while this was partly attenuated by 4MP, DAS had no effect. DAS in combination with EtOH increased the number of hepatocytes in S-phase (p < 0.05). These data suggest that oxidative stress and many of the cytokine changes associated with hepatic injury following EtOH exposure are not mediated via CYP2E1 or acetaldehyde, but that EtOH metabolism by CYP2E1 may be linked to induction of TNF', whereas acetaldehyde production may be linked in part to necrosis, chemokine production,and ER stress.

Last Modified: 8/1/2014
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