EC-SOD gene therapy reduces paracetamol-induced liver damage in mice.
BACKGROUND
Paracetamol overdose causes acute liver damage which leads to severe centrilobular hepatic necrosis. The hepatotoxic effect is caused by reactive metabolites and oxidative stress. Since extracellular superoxide dismutase (EC-SOD) protects tissues against the harmful effects of superoxide anion, the hypothesis that systemic adenovirus-mediated EC-SOD gene transfer could reduce liver damage was tested.


METHODS
Mice were given paracetamol (600 mg/kg) enterally 2 days after adenovirus-mediated gene transfer of EC-SOD (2 x 10(9) pfu). Five days after gene transfer, plasma and tissue samples were collected for clinical chemistry analyses and tissue pathology evaluation.


RESULTS
EC-SOD was expressed in a dose-dependent manner with the highest enzyme activity occurring 3 days after the gene transfer. Clinical chemistry and tissue pathology analyses showed that adenoviral EC-SOD gene transfer significantly attenuated release of liver enzymes and inhibited necrosis and apoptosis caused by paracetamol overdose.


CONCLUSIONS
The results indicate the involvement of superoxide anion in paracetamol-mediated liver damage and suggest a possible protective role for EC-SOD gene transfer in paracetamol-induced liver damage.
Laukkanen
M O
MO
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland.
Leppanen
P
P
Turunen
P
P
Tuomisto
T
T
Naarala
J
J
Yla-Herttuala
S
S
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D006520:Hepatitis, Animal / Q000139:chemically induced* / Q000473:pathology / Q000628:therapy; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000494:pharmacology; D013997:Time Factors
D011994:Recombinant Proteins; D000082:Acetaminophen; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases