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 (WD). 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 (HCC). 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 (LEA) 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.

Beneath the Copper—Pediatric Wilson's Disease Cirrhosis and Hepatocellular Carcinoma: A Case Report with Literature Review

“…22 Furthermore, the LEC rat model has demonstrated that oxidative stress mediates the functional loss of a DNA base excision repair pathway enzyme, apurinic/apyrimidinic endonuclease 1 (APE1) that has been associated with liver tumorigenesis. 23 The growth of WD-related malignancy may be iron dependent because an iron-deficient diet prevented the development of well-differentiated adenocarcinoma in this animal model. 24 Intra-abdominal malignancies related to WD such as HCC, cholangiocarcinoma and adenocarcinoma have been described in several large WD cohorts.…”