Long-term effects of peroxisome proliferators on the balance between hydrogen peroxide-generating and scavenging capacities in the liver of Fischer-344 rats.
In order to clarify whether peroxisomal hydrogen peroxide (H2O2) plays an important role in peroxisome proliferator-induced hepatocarcinogenesis, we examined the change in metabolism of peroxisomal H2O2 in vivo and in vitro using male Fischer-344 rats fed clofibrate, bezafibrate and di(2-ethylhexyl)phthalate (DEHP) for up to 78 weeks. Hepatic peroxisomal fatty acyl-CoA oxidase activity increased 12-20-fold after 2 or 4 weeks treatment; later this level gradually decreased toward controls, and at 78 weeks activity was 3-10-times of control. Although hepatic H2O2 levels were increased slightly by clofibrate, bezafibrate and DEHP, the changes did not correlate with the changes in peroxisomal fatty acyl-CoA oxidase activity. In isolated hepatocytes, the rate of leakage of peroxisomal H2O2 from peroxisomes into the cytosol and the hepatocellular H2O2 content was measured. The rate of leakage of peroxisomal H2O2 into cytosol increased 2.5-4-fold when peroxisomal beta-oxidation activity was induced by peroxisome proliferators, and the increases in this rate corresponded with changes in the peroxisomal beta-oxidation activity. In contrast, the hepatocellular H2O2 contents were not affected by induced peroxisomal beta-oxidation. These data show that H2O2 leaking from peroxisome into cytosol would be quickly decomposed, and thus peroxisomal H2O2 does not appear to play an important role in hepatocarcinogenesis by such an oxidative stress mechanism after the long-term treatment with peroxisome proliferators.
Department of Clinical Biochemistry, Tokyo College of Pharmacy, Japan.
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Tamura
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Iida
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Watanabe
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Suga
D042962:Acyl-CoA Oxidase; D000818:Animals; D001629:Bezafibrate / Q000633:toxicity*; D002478:Cells, Cultured; D002994:Clofibrate / Q000633:toxicity*; D003600:Cytosol / Q000032:analysis; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008114:Liver Neoplasms, Experimental / Q000032:analysis / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D010088:Oxidoreductases / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D010795:Phthalic Acids; D006861:Hydrogen Peroxide; D004051:Diethylhexyl Phthalate; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D002994:Clofibrate; D001629:Bezafibrate