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

Abstract

Increased oxidative DNA damage due to increased peroxisomal generation of H2O2 is a potential mechanism in the carcinogenicity of chemical peroxisome proliferators (PP) in rodent liver. In order to determine the relationship between carcinogenicity and peroxisome-dependent DNA damage, levels of DNA base oxidation were examined by comparing 8-hydroxydeoxyguanosine (8-OHdG) in DNA from unfractionated liver of male F344 rats following dietary 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 3 or 11 weeks for any of the compounds fed. At 22 weeks, 8-OHdG was similarly elevated (2-3x) by WY-14,643 (0.1% and 0.005%) and clofibric acid (0.5%). These equivalent increases in 8-OHdG in DNA from unfractionated liver did not parallel the divergent carcinogenicity of these different dietary exposures in the present or previous studies. The potential oxidation of nuclear DNA was examined by comparing levels of 8-OHdG in DNA isolated from purified liver nuclei and unfractionated liver. Elevated levels of 8-OHdG were not detected in DNA isolated from nuclear fractions of livers from rats fed clofibric acid for 22 weeks, indicating the dependence of PP-induced oxidative DNA damage on extranuclear components of samples for DNA isolation. The absence of a quantitative relationship between PP-induced carcinogenicity and oxidative DNA base damage (as 8-OHdG), and the 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-dependent DNA damage and carcinogenicity of PP exposure in rodents; (2) other hepatic responses may be more critical features of the mechanism of PP carcinogenicity.

Molecular basis of vanadium‐mediated inhibition of hepatocellular preneoplasia during experimental hepatocarcinogenesis in rats

“…Induction of significant and high steady levels of 8-OHdGs essentially plays a critical role for the activation of carcinogenic properties of cells [Floyd, 1990;Cattley and Glover, 1993;Shen et al, 1995]. Using the sensitive HPLC-ECD method, we detected here a substantial level of 8-OHdGs in hepatic DNA of rats treated with DEN over the vehicle control that supported this concept.…”

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

“…A number of indirect confirmations for DEHP-initiated increases in oxidants have been collected over past two decades [120,121,122,123,124,125]. It should be noted, however, that causative relevance of some of such evidence to the carcinogenic effect of PP in general, and DEHP in particular, has been questioned and contrasting views have been presented [126,127,128,129,130]. It has been shown that PPARα is required for generation of oxidants in mouse liver after prolonged [weeks, [131]], but not acute [hours, [132]] exposure to PPs.…”

Health risks posed by use of Di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: A critical review

“…While these two processes together may largely explain the mechanism of the carcinogenic response [Reddy and Lalwani, 1983;Doull et al, 1999], some research indicates that there may be other important factors such as indirect genotoxicity; effects on cell transformation and intercellular communication; and other non-peroxisomal parameters such as mitrochondrial effects and effects on enzyme activity [Cattley and Glover, 1993;Melnick and Cohen, 1996;Gonzalez et al, 1998;KemI, 1999]. For example, DEHP and diethylhexyl adipate, which result in similar levels of peroxisomal induction in rats do not lead to similar tumogenic responses [Melnick and Kohn, 1996].…”