Abstract |
To elucidate the role of metal-related molecules in hepatocarcinogenesis, we examined immunolocalization of transferrin receptor (Tfrc), ceruloplasmin (Cp) and metallothionein (MT)-1/2 in relation to liver cell foci positive for glutathione-S-transferase placental form (GST-P) in the early stage of tumor promotion by fenbendazole (FB), phenobarbital, piperonyl butoxide or thioacetamide in a rat two-stage hepatocarcinogenesis model. To estimate the involvement of oxidative stress responses to the promotion, immunolocalization of 4-hydroxy-2-nonenal, malondialdehyde and acrolein was similarly examined. Our findings showed that MT-1/2 immunoreactivity was not associated with the cellular distribution of GST-P and proliferating cell nuclear antigen, suggesting no role of MT-1/2 in hepatocarcinogenesis. We also found enhanced expression of Tfrc after treatment with strong tumor-promoting chemicals. With regard to Cp, the population showing down-regulation was increased in the GST-P-positive foci in relation to tumor promotion. Up-regulation of Tfrc and down-regulation of Cp was maintained in GST-P-positive neoplastic lesions induced after long-term promotion with FB, suggesting the expression changes occurring downstream of the signaling pathway involved in the formation of GST-P-positive lesions. Furthermore, enhanced accumulation of lipid peroxidation end products was observed in the GST-P-positive foci by promotion. Post-initiation treatment with peroxisome proliferator-activated receptor alpha agonists did not enhance any such distribution changes in GST-P-negative foci. The results thus suggest that facilitation of lipid peroxidation is involved in the induction of GST-P-positive lesions by tumor promotion from an early stage, and up-regulation of Tfrc and down-regulation of Cp may be a signature of enhanced oxidative cellular stress in these lesions.
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Authors | Sayaka Mizukami, Ryohei Ichimura, Sayaka Kemmochi, Eriko Taniai, Keisuke Shimamoto, Takumi Ohishi, Miwa Takahashi, Kunitoshi Mitsumori, Makoto Shibutani |
Journal | Archives of toxicology
(Arch Toxicol)
Vol. 84
Issue 4
Pg. 319-31
(Apr 2010)
ISSN: 1432-0738 [Electronic] Germany |
PMID | 20091025
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carcinogens
- PPAR alpha
- Receptors, Transferrin
- Copper
- Metallothionein
- Iron
- Ceruloplasmin
- Glutathione S-Transferase pi
- Gstp1 protein, rat
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Topics |
- Animals
- Carcinogenicity Tests
- Carcinogens
- Ceruloplasmin
(metabolism)
- Copper
(metabolism)
- Disease Models, Animal
- Down-Regulation
- Gene Expression Regulation, Neoplastic
- Glutathione S-Transferase pi
(metabolism)
- Iron
(metabolism)
- Lipid Peroxidation
- Liver
(metabolism)
- Liver Neoplasms, Experimental
(etiology, metabolism)
- Male
- Metallothionein
(metabolism)
- Oxidative Stress
- PPAR alpha
(metabolism)
- Rats
- Rats, Inbred F344
- Receptors, Transferrin
(metabolism)
- Up-Regulation
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