The hepatic levels of three protein markers of oxidative stress, polymerase beta, Ref-1, and PCNA, and of the pro-apoptotic protein, Bax, were quantitated after exposure to WY 14,643 (500 ppm in the feed) for 6 or 34 days in a rodent that is susceptible peroxisome proliferator (PP)-induced liver tumors (the Sprague Dawley rat) and in a rodent that is relatively resistant PP-induced liver tumors (the Syrian hamster). The analysis of detergent-extracted whole liver homogenates by immunoblotting showed a marked increase in the abundance of a 45-kDa variant of polymerase beta immunoreactivity and significant increases in the expression of Ref-1 and PCNA in WY 14,643-exposed rats. In contrast. WY 14,643-exposed hamsters expressed only trace levels of the polymerase beta variant and showed significant decreases in the expression of Ref-1 and PCNA. Long-term WY 14,643 exposure was associated with marked decreases in Bax expression in both species. Dose-response studies in the rat showed that the hepatic expression of the polymerase beta and Ref-1 were significantly increased after 6 days of exposure to WY 14,643 at levels of 5 and 50 ppm, respectively. The analysis of subcellular fractions of rat liver showed that the pathological increases in the levels of polymerase beta, Ref-1, and PCNA were especially prominent in mitochondria-enriched particulate liver subfractions. These results indicate that WY 14,643 exposure is associated with an increase in oxidative stress to the liver and that liver mitochondria are a major target of WY 14,643-associated liver damage. Our data are consistent with the hypothesis that the chronic overexpression of mutagenic or oncogenic effectors like polymerase beta and Ref-1 in a setting of increased hepatocyte proliferation and decreased apoptosis may facilitate peroxisome proliferator-induced hepatocellular carcinoma in the rat.