Increased hydroxyl radical production in liver peroxisomal fractions from rats treated with peroxisome proliferators.
Electron spin resonance (e.s.r.), using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), has been employed to measure hydroxyl radical production in liver peroxisome-enriched fractions isolated from male Alpk/Ap rats administered chemicals known to cause peroxisome proliferation. The DMPO-OH adduct was found to decay to an e.s.r. silent species so rapidly in the presence of the native peroxisome-enriched fraction as to preclude any measurements in this system. All of the experiments were therefore carried out in the presence of cyanide in order to visualise the DMPO-OH adducts, although a consequence of this was the inhibition of the peroxisomal catalase activity. The DMPO-OH adduct was identified in fractions from both control and treated animals in the presence of palmitoyl CoA as substrate and was found to be present at 3-4 times the control value in animals orally administered di(2-ethylhexyl)phthalate (2000 mg/kg), clofibrate (200 mg/kg) or methyl clofenapate (25 mg/kg) for 9 days. The rate of production of hydroxyl radicals was also greater in fractions from treated animals. The fatty acyl CoA oxidase system of liver peroxisome-enriched fractions has now been shown to produce increased levels of hydrogen peroxide and hydroxyl radicals in the presence of a suitable substrate. Despite such evidence from in vitro enzyme systems, evidence of genotoxicity in vivo is still required to confirm the hypothesis linking such reactive oxygen species to the carcinogenicity observed in rodents with certain peroxisome proliferators.
D000818:Animals; D001386:Azides / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D003486:Cyanides / Q000633:toxicity; D003497:Cyclic N-Oxides; D004247:DNA; D004578:Electron Spin Resonance Spectroscopy; D006861:Hydrogen Peroxide / Q000633:toxicity; D006878:Hydroxides / Q000378:metabolism*; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D004369:Pentetic Acid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001386:Azides; D003486:Cyanides; D003497:Cyclic N-Oxides; D006878:Hydroxides; D017665:Hydroxyl Radical; C017245:5,5-dimethyl-1-pyrroline-1-oxide; D004369:Pentetic Acid; D004247:DNA; D006861:Hydrogen Peroxide