Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats.
OBJECTIVE
Alcohol-induced liver injury is associated with an increase in oxidants from a variety of possible sources. Therefore, it was hypothesized that increased and stable expression of the antioxidant enzyme Cu/Zn-superoxide dismutase (SOD1) would diminish oxygen free radicals and reduce alcohol-induced liver injury.


METHODS
To test this hypothesis, rats were given recombinant adenovirus containing Cu/Zn-superoxide dismutase (Ad.SOD1) or beta-galactosidase (Ad.lacZ) and fed ethanol enterally for 3 weeks.


RESULTS
SOD was increased significantly 3-5-fold over endogenous levels in both hepatocytes as well as Kupffer cells 3 weeks after infection. Serum transaminase levels and pathology were elevated significantly in Ad.lacZ-treated animals by using an intragastric feeding model. This effect was blunted significantly in Ad.SOD1-infected animals. Importantly, electron spin resonance-detectable free-radical adducts caused by ethanol were also decreased by SOD1 overexpression. Moreover, the increase in nuclear factor kappaB (NFkappaB), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 messenger RNA (mRNA) caused by ethanol was blunted in animals treated with Ad.SOD1.


CONCLUSIONS
These data support the hypothesis that oxidant production is critical in early alcohol-induced liver injury and that gene delivery of antioxidant enzymes may be useful in prevention and treatment.
Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. wheelmi@med.unc.edu
M D
MD
Wheeler
H
H
Kono
M
M
Yin
I
I
Rusyn
M
M
Froh
H D
HD
Connor
R P
RP
Mason
R J
RJ
Samulski
R G
RG
Thurman
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D007375:Interleukin-1 / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000628:therapy*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D002492:Central Nervous System Depressants; D005609:Free Radicals; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D013482:Superoxide Dismutase