Elevated 8-hydroxydeoxyguanosine in hepatic DNA of rats following exposure to peroxisome proliferators: relationship to carcinogenesis and nuclear localization

Increased oxidative DNA damage due to increased peroxisomalgeneration of H₂O₂ is a potential mechanism in the carcinogenicityof chemical peroxisome proliferators (PP) in rodent liver. Inorder to determine the relationship between carcinogencity andperoxisome-dependent DNA damage, levels of DNA base oxidationwere examined by comparing 8-hydroxydeoxyguanosine (8-OHdG)in DNA from unfractionated liver of male F344 rats followingdietary exposure to PP [WY-14, 643, 0.1% or 0.005%; di(2-ethylhexyl)phthalate(DEHP), 1.2%; clofibric acid, 0.5%] or phenobarbital (0.05%).Exposure-related increases in 8-OHdG were not observed at 3or 11 weeks for any of the compounds fed. At 22 weeks, 8-OHdGwas similarly elevated (2–3x) by WY-14, 643 (0.1% and0.005%) and clofibric acid (0.5%). These equivalent increasesin 8-OHdG in DNA from unfractionated liver did not parallelthe divergent carcinogencity of these different dietary exposuresin the present or previous studies. The potential oxidationof nuclear DNA was examined by comparing levels of 8-OHdG inDNA isolated from purified liver nuclei and unfractionated liver.Elevated levels of 8-OHdG were not detected in DNA isolatedfrom nuclear fractions of livers from rats fed clofibric acidfor 22 weeks, indicating the dependence of PP-induced oxidativeDNA damage on extranuclear components of samples for DNA isolation.The absence of a quantitative relationship between PP-inducedcarcinogenicity and oxidative DNA base damage (as 8-OHdG), andthe failure to localize this oxidative damage to nuclear DNA,suggest two possible conclusions: (1) quantitation of 8-OHdG,a specific and sensitive indicator of oxidative DNA damage,does not accurately reflect the potential peroxisomal H₂O₂-dependentDNA damage and carcinogenicity of PP exposure in rodents; (2)other hepatic responses may be more critical features of themechanism of PP carcinogenicity.