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Molecular and Cellular Biochemistry

, Volume 388, Issue 1–2, pp 185–193 | Cite as

Redox regulation of apurinic/apyrimidinic endonuclease 1 activity in Long-Evans Cinnamon rats during spontaneous hepatitis

  • Soumendra Krishna Karmahapatra
  • Tapas Saha
  • Sanjay Adhikari
  • Jordan Woodrick
  • Rabindra Roy
Article

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.

Keywords

APE1 DNA damage DNA repair HCC 

Abbreviation

LEC

Long-Evans Cinnamon

LEA

Long-Evans Agouti

APE1

AP-endonuclease 1

ROS

Reactive oxygen species

WD

Wilson’s disease

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

Notes

Acknowledgments

We thank Dr. Sujata Choudhury and Praveen Manthena for technical assistance in some initial experiments. The work was supported by the National Institutes of Health RO1 Grants CA 113447 and CA 92306 (RR).

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Soumendra Krishna Karmahapatra
    • 1
  • Tapas Saha
    • 1
  • Sanjay Adhikari
    • 1
  • Jordan Woodrick
    • 1
  • Rabindra Roy
    • 1
  1. 1.Department of OncologyLombardi Comprehensive Cancer Center, Georgetown University Medical School, Georgetown University Medical CenterWashingtonUSA

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