In vitro steady-state levels of hydrogen peroxide after exposure of male F344 rats and female B6C3F1 mice to hepatic peroxisome proliferators.
The hypothesis that hepatocarcinogenesis resulting from treatment of rats and mice with peroxisome proliferators is linked to increased cellular levels of hydrogen peroxide from peroxisomal beta-oxidation was investigated. Male F344 rats and female B6C3F1 mice were treated for 14 days with di(2-ethylhexyl)phthalate (DEHP) or di(2-ethylhexyl)adipate (DEHA), industrial plasticizers, or nafenopin, a hypolipidemic drug. Activities of enzymes responsible for the production [peroxisomal palmitoyl CoA oxidase (PCO)] and degradation [catalase (Cat) and glutathione peroxidase (GSHPx)] of H2O2 were assayed in liver homogenates prepared from treated animals. The activities of the peroxisomal enzymes PCO and Cat were enhanced 5- to 25-fold and 1.5- to 3-fold respectively by treatment with the peroxisome proliferators. The activity of GSHPx, a cytoplasmic enzyme, was decreased 40-60% in liver homogenates prepared from treated animals compared to control animals. A kinetic treatment of the rates of formation of hydrogen peroxide by PCO, and of degradation of hydrogen peroxide by catalase was used to estimate steady-state hydrogen peroxide concentrations ([H2O2]) during peroxisomal oxidation of palmitoyl CoA. Increases in peroxisomal steady-state [H2O2] for the F344 rat liver homogenates correlated well with the carcinogenic potential of these chemicals, determined in previous carcinogenicity studies. Increases in the steady-state [H2O2] were also calculated for liver homogenates prepared from mice treated with these compounds. Decreases in liver lipid peroxidation were observed after treatment with each chemical in both species. The results of these studies are consistent with an involvement of increased peroxisomal hydrogen peroxide in the hepatocarcinogenesis of these compounds.
D000272:Adipates / Q000633:toxicity; D000818:Animals; D002374:Catalase / Q000032:analysis; D002455:Cell Division / Q000187:drug effects; D004249:DNA Damage; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D005260:Female; D005979:Glutathione Peroxidase / Q000032:analysis; D006861:Hydrogen Peroxide / Q000032:analysis*; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008830:Microbodies / Q000187:drug effects*; D009255:Nafenopin / Q000633:toxicity; D010088:Oxidoreductases / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344
D000272:Adipates; D008054:Lipid Peroxides; D009255:Nafenopin; C013966:dioctyl adipate; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate; D010088:Oxidoreductases; D002374:Catalase; D005979:Glutathione Peroxidase; C028427:palmitoyl CoA oxidase