Progression of Hepatic Adenoma to Carcinoma in Ogg1 Mutant Mice Induced by Phenobarbital

The carcinogenic potential of phenobarbital (PB) was assessed in a mouse line carrying a mutant Mmh allele of the Mmh/Ogg1 gene encoding the enzyme oxoguanine DNA glycosylase (Ogg1) responsible for the repair of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Mmh homozygous mutant (Ogg1(−/−)) and wild-type (Ogg1(+/+)) male and female, 10-week-old, mice were treated with 500 ppm PB in diet for 78 weeks. Hepatocellular carcinomas (HCCs) were found in PB-treated Ogg1(−/−) mice, while Ogg1(+/+) animals developed only hepatocellular adenomas (HCAs) at the same rate. This was coordinated with PB-induced significant elevation of 8-OHdG formation in DNA and cell proliferation in adjacent liver of Ogg1(−/−) mice. Proteome analysis predicted activation of transcriptional factor Nrf2 in the livers and HCAs of PB-administered Ogg1(+/+) mice; however, its activation was insufficient or absent in the livers and HCCs of Ogg1(−/−) mice, respectively. Significant elevation of phase I and II metabolizing enzymes was demonstrated in both Ogg1(−/−) and Ogg1(+/+) animals. Treatment of Ogg1(−/−) mice with PB resulted in significant elevation of cell proliferation in the liver. These results indicate that PB induced progression from HCA to HCC in Ogg1(−/−) mice, due to persistent accumulation of DNA oxidative base modifications and suppression of Nrf2-mediated oxidative stress response, resulting in significant elevation of cell proliferation.