title: Redox regulation of apurinic/apyrimidinic endonuclease 1 activity in Long-Evans Cinnamon rats during spontaneous hepatitis.
abstract: The Long-Evans Cinnamon (LEC) rat is an animal model for Wilson's disease. This animal is genetically predisposed to copper accumulation in the liver, increased oxidative stress, accumulation of DNA damage, and the spontaneous development of hepatocellular carcinoma. Thus, this animal model is useful for studying the relationship of endogenous DNA damage to spontaneous carcinogenesis. In this study, we have investigated the apurinic/apyrimidinic endonuclease 1 (APE1)-mediated excision repair of endogenous DNA damage, apurinic/apyrimidinic (AP)-sites, which is highly mutagenic and implicated in human cancer. We found that the activity was reduced in the liver extracts from the acute hepatitis period of LEC rats as compared with extracts from the age-matched Long-Evans Agouti rats. The acute hepatitis period had also a heightened oxidative stress condition as assessed by an increase in oxidized glutathione level and loss of enzyme activity of glyceraldehyde 3-phosphate dehydrogenase, a key redox-sensitive protein in cells. Interestingly, the activity reduction was not due to changes in protein expression but apparently by reversible protein oxidation as the addition of reducing agents to extracts of the liver from acute hepatitis period reactivated APE1 activity and thus, confirmed the oxidation-mediated loss of APE1 activity under increased oxidative stress. These findings show for the first time in an animal model that the repair mechanism of AP-sites is impaired by increased oxidative stress in acute hepatitis via redox regulation which contributed to the increased accumulation of mutagenic AP-sites in liver DNA.
authors: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, Georgetown University Medical Center, LL level, S-122 3800 Reservoir Road, NW, Washington, DC, 20057, USA.
authors: Soumendra Krishna
authors: SK
authors: Karmahapatra
authors: Tapas
authors: T
authors: Saha
authors: Sanjay
authors: S
authors: Adhikari
authors: Jordan
authors: J
authors: Woodrick
authors: Rabindra
authors: R
authors: Roy
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D003300:Copper; D000073840:Copper-Transporting ATPases; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006520:Hepatitis, Animal / Q000235:genetics*; D007249:Inflammation; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D020332:Rats, Inbred LEC; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D017382:Reactive Oxygen Species; D003300:Copper; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+); D000251:Adenosine Triphosphatases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C550619:Atp7b protein, rat; D000073840:Copper-Transporting ATPases