title: Chronic ethanol consumption results in atypical liver injury in copper/zinc superoxide dismutase deficient mice.
abstract: BACKGROUND
  Ethanol metabolism increases production of reactive oxygen species, including superoxide (O2(.-)) in the liver, resulting in significant oxidative stress, which causes cellular damage. Superoxide dismutase (SOD) is an antioxidant enzyme that converts superoxide to less toxic intermediates, preventing accumulation. Because the absence of SOD would confer less resistance to oxidative stress, we determined whether damage to hepatic proteolytic systems was greater in SOD(-/-) than in SOD(+/+) mice after chronic ethanol feeding.
  
  
  METHODS
  Female wild-type (SOD(+/+)) and Cu/Zn-SOD knockout (SOD(-/-)) mice were pair-fed ethanol and control liquid diets for 24 days, after which liver injury was assessed.
  
  
  RESULTS
  Ethanol-fed SOD(-/-) mice had 4-fold higher blood ethanol, 2.8-fold higher alanine aminotransferase levels, 20% higher liver weight, a 1.4-fold rise in hepatic protein levels, and 35 to 70% higher levels of lipid peroxides than corresponding wild-type mice. While wild-type mice exhibited fatty liver after ethanol administration, SOD(-/-) mice showed no evidence of ethanol-induced steatosis, although triglyceride levels were elevated in both groups of knockout mice. Ethanol administration caused no significant change in proteasome activity, but caused lysosomal leakage in livers of SOD(-/-) mice but not in wild-type mice. Alcohol dehydrogenase activity was reduced by 50 to 60% in ethanol-fed SOD(-/-) mice compared with all other groups. Additionally, while ethanol administration induced cytochrome P450 2E1 (CYP2E1) activity in wild-type mice, it caused no such induction in SOD(-/-) mice. Unexpectedly, ethanol feeding significantly elevated total and mitochondrial levels of glutathione in SOD knockout mice compared with wild-type mice.
  
  
  CONCLUSIONS
  Ethanol-fed SOD(-/-) mice exhibited lower alcohol dehydrogenase activity and lack of CYP2E1 inducibility, thereby causing decreased ethanol metabolism compared with wild-type mice. These and other atypical responses to ethanol, including the absence of ethanol-induced steatosis and enhanced glutathione levels, appear to be linked to enhanced oxidative stress due to lack of antioxidant enzyme capacity.
authors: Liver Study Unit, Omaha Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska, USA. tcurry@emory.edu
authors: Tiana V
authors: TV
authors: Curry-McCoy
authors: Natalia A
authors: NA
authors: Osna
authors: Amin A
authors: AA
authors: Nanji
authors: Terrence M
authors: TM
authors: Donohue
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000378:metabolism / Q000633:toxicity*; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008055:Lipids / Q000097:blood; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics*
chemical_list: D000975:Antioxidants; D002492:Central Nervous System Depressants; D008055:Lipids; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D013482:Superoxide Dismutase; D000410:Alanine Transaminase; D053148:Caspase 3; D002401:Cathepsin B; D056668:Cathepsin L; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione