Tumor promotion by copper-overloading and its enhancement by excess iron accumulation involving oxidative stress responses in the early stage of a rat two-stage hepatocarcinogenesis model.

Abstract

To investigate liver tumor promotion mechanisms of copper (Cu)- and iron (Fe)-overloading, immunolocalization of metal-related biomolecules and lipid peroxidation end products was examined in preneoplastic liver cell foci that expressed glutathione S-transferase placental form (GST-P) in early-stage tumor promotion over 6 weeks in a rat two-stage hepatocarcinogenesis model. Gene expression and concentrations of thiobarbituric acid-reactive substance (TBARS) in the liver were also analyzed. Cu-overloading alone exerted a weak promoting activity, which was enhanced by Fe-overloading. By Cu-overloading, GST-P(+) foci that co-expressed transferrin receptors or downregulated ceruloplasmin increased, suggesting preneoplastic lesion-specific enhancement of oxidative cellular stress. Cu-overloading also increased transcripts of antioxidant enzymes (Gstm3 and Gst Yc2 subunit), cell proliferation, and numbers of single liver cells expressing GST-P or heme oxygenase-1 (HO-1) in the liver, suggesting that oxidative stress induces single-cell toxicity, with the ensuing regeneration contributing to tumor promotion. Fe-overloading increased liver TBARS and HO-1-expressing Kupffer cells, the latter suggesting protection against inflammatory stimuli causing fluctuating proinflammatory cytokine mRNA levels. By co-overloading of Cu and Fe, Cu-overload-related single liver cell toxicity and regeneration increased, as did cytokine imbalances involving increased cyclooxygenase-2-producing Kupffer cells and accumulation of malondialdehyde within GST-P(+) foci. These results suggest an involvement of oxidative stress responses in Cu-induced tumor promotion and Fe-induced enhancement by increasing cytokine imbalances and GST-P(+) foci-specific lipid peroxidation.

• Authors: Sayaka Mizukami, Ryohei Ichimura, Sayaka Kemmochi, Liyun Wang, Eriko Taniai, Kunitoshi Mitsumori, Makoto Shibutani
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 185 Issue 3 Pg. 189-201 (May 14 2010) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 20302851 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Carcinogens
• Thiobarbituric Acid Reactive Substances
• Diethylnitrosamine
• Copper
• Iron
• Glutathione Transferase

Topics

• Animals
• Carcinogenicity Tests
• Carcinogens (toxicity)
• Copper (metabolism)
• Diethylnitrosamine (toxicity)
• Glutathione Transferase (metabolism)
• Immunohistochemistry
• Iron (metabolism)
• Iron Overload (metabolism)
• Liver (enzymology, metabolism, pathology)
• Liver Neoplasms, Experimental (metabolism, pathology)
• Male
• Oxidative Stress
• Rats
• Rats, Inbred F344
• Thiobarbituric Acid Reactive Substances (analysis, metabolism)
• Time Factors