Transgene expression of human PON1 Q in mice protected the liver against CCl4-induced injury.
BACKGROUND
Oxidative stress, often in association with decreased antioxidant defenses, plays a pathogenetic role in both initiation and progression of liver injuries, leading to almost all clinical and experimental conditions of chronic liver diseases. Human paraoxonase 1 (hPON1) is a liver-synthesized enzyme possessing antioxidant properties. Here, we investigate the effects of transgene-expressed hPON1 Q on alleviating lipid peroxidation and preventing liver injury in a mouse model.


METHODS
The hPON1 Q gene was cloned into pcDNA3.0 plasmid and electro-transferred into mouse skeletal muscle. After CCl4 had been administrated to induce liver injury, mice were monitored for serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and malonyldialdehyde (MDA). The extent of CCl4-induced liver injury was also analyzed through histopathological observations.


RESULTS
After gene delivery, hPON1 mRNA expression was detected in mouse muscle and serum PON1 activity was 1.5 times higher than that of the control counterpart. In the PON1 Q gene transferred mice, protection against CCl4-induced liver injury was reflected by significantly decreased serum ALT, AST and MDA levels compared to those in control mice (P < 0.01). Histological observations also revealed that hepatocyte necrosis, hemorrhage, vacuolar change and hydropic degeneration were apparent in control mice after CCl4 administration. In contrast, the damage was significantly prevented (P < 0.01) in the hPON1 Q transferred mice.


CONCLUSIONS
Intramuscular electro-transfer of the hPON1 Q gene led to efficient expression of hPON1 in mice. Elevated levels of PON1, by virtue of its potency to alleviate oxidative stress, could protect mice from suffering CCl4-induced liver damage.
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, PR China.
Chi
C
Zhang
Wei
W
Peng
Xiaoling
X
Jiang
Bo
B
Chen
Jie
J
Zhu
Yuhui
Y
Zang
Junfeng
J
Zhang
Tongyang
T
Zhu
Junchuan
J
Qin
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D043303:Aryldialkylphosphatase / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D002251:Carbon Tetrachloride; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008107:Liver Diseases / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D008315:Malondialdehyde; D051379:Mice; D008813:Mice, Inbred ICR; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D010957:Plasmids; D019076:Transgenes / Q000235:genetics*
D008315:Malondialdehyde; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human