Unusual Generation of Hydroxyl Radicals in Hepatic Copper-Metallothionein of LEC (Long-Evans Cinnamon) Rats in the Presence of Hydrogen Peroxide

Satoh, Hiromi; Hatanaka, Akikazu; Sawada, Tânia Cristina Higashi; Kawano, Kazuya; Hagino, T.; Nakajima, Katsuyuki

doi:10.1006/bbrc.1994.1230

Cited by 50 publications

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“…They suggest the increased free radical produced by Cu-MT in hepatocyte may cause hepatic injury. 5) In this study, it was found that the quantity of Cu, which is higher in human HCC, exists in the form of Cu-MT, as it does in LEC rats. We believe that it is important to investigate the relationship between the development of HCC and free radical generation by Cu-MT.…”

Section: Discussionmentioning

confidence: 69%

“…5,9,10,16) Because of their congenital anomaly of Cu metabolism, abnormal copper accumulation in the hepatic tissue, and spontaneous hepato-oncogenesis, LEC rats are used as animal models for Wilson's disease and HCC. Sakurai et al reported that the Cu-MT level increases markedly in the hepatocytes of LEC rats 16) and that this Cu-MT produces hydroxyl radicals by Fenton-like reaction.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…5) Because Cu-MT forms a hydroxyl radical through the Fenton-like reaction, Sakurai et al suspected that Cu-MT acts as a radical promoter. 5) Gel-filtration analysis of Cu and Zn distribution in the MT fraction has been conducted using liver tissue from newborn rats, guinea pigs, and other mammals. [6][7][8] Suzuki et al used the high-performance liquid chromatography (HPLC) to accurately analyze the distribution patterns of Cu and Zn in MT and superoxide dismutase (SOD) in LEC rats before and after the onset of acute hepatic injury.…”

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confidence: 99%

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Evaluation of Distribution Patterns for Copper and Zinc in Metallothionein and Superoxide Dismutase in Chronic Liver Diseases and Hepatocellular Carcinoma Using High-Performance Liquid Chromatography (HPLC)

Kubo

Fukuda

Ebara

et al. 2005

Biological & Pharmaceutical Bulletin

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Metallothionein (MT) was initially discovered from a horse kidney in 1957 as a protein that contained cadmium. Metallothionein is a heat-stable, metal-binding protein with a molecular weight of 6500 to 7000. 1) A number of physiological and biological roles have been suggested for MT, including detoxification of heavy metals, metabolic regulation of Zinc (Zn) and Copper (Cu) (two trace elements that are essential to the body), and a radical-scavenging action that is closely related to the biological defense mechanism.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of Distribution Patterns for Copper and Zinc in Metallothionein and Superoxide Dismutase in Chronic Liver Diseases and Hepatocellular Carcinoma Using High-Performance Liquid Chromatography (HPLC)

Kubo

Fukuda

Ebara

et al. 2005

Biological & Pharmaceutical Bulletin

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“…25) It has been suggested that hepatic metallothionein-bound copper in LEC rats generates hydroxy-radicals in the presence of hydrogen peroxide in the cells. 26) We measured the total copper and iron concentrations in these organs.…”

Section: Discussionmentioning

confidence: 99%

Role of Copper Accumulation in Spontaneous Renal Carcinogenesis in Long‐Evans Cinnamon Rats

Kitaura

Chone

Satake

et al. 1999

Japanese Journal of Cancer Research

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Spontaneous renal cell tumors in totals of 223 male and female Long-Evans Cinnamon (LEC) rats of 51-120 weeks old, 157 male F344 rats of 51-120 weeks old, and 14 male Long-Evans Agouti (LEA) rats of 51-70 weeks old were examined histologically. The incidences of renal cell tumors increased with age in male and female LEC rats, but no tumors developed in F344 or LEA rats. Dilated atypical tubules of the kidneys were observed at high incidence in aged LEC rats. Copper staining of LEC rat kidneys showed a positive reaction in proximal tubules of the cortex and the outer stripe of the medulla. The renal copper concentration of LEC rats reached a peak in the period of necrotizing hepatitis with renal tubular necrosis, and was higher than that in F344 rats for up to 106 weeks. In contrast, the renal iron concentration of LEC rats was lower than that in F344 rats except in the period of necrotizing hepatitis. Long-term treatment of LEC rats with Dpenicillamine, a copper-chelating agent, inhibited accumulation of copper, but not iron, in the kidneys, and inhibited the development of karyomegaly of proximal tubules and dilated atypical tubules. These results suggest that persistent copper accumulation after toxic necrosis of tubules is the major cause of spontaneous renal carcinogenesis in LEC rats. Key words: Renal carcinogenesis -Spontaneous -Copper -LEC ratThe LEC rat is an inbred strain showing abnormally high copper accumulation in the liver, 1) and has a deletion in the copper-transporting ATPase gene (Atp7b)2) homologous to the human Wilson's disease gene. This mutant rat strain was originally isolated from a closed colony of Long-Evans rats.3) LEC rats develop necrotizing hepatitis with jaundice 4 to 6 months after birth and this hepatitis is inherited in an autosomally recessive manner. 4) About 20-50% of these rats die of fulminant hepatitis, and hepatocellular carcinomas develop in rats of 12 months old or more that recover from the liver injury.4-6) Both the hepatitis and hepatocellular carcinomas can be prevented by treatment with the copper-chelating agent, D-penicillamine or trientine. 7,8) Patients with Wilson's disease are known to have abnormal renal function and penicillamine therapy improves their renal function, 9) but we know of no reports of renal neoplasms in cases of Wilson's disease. We have reported that renal cell tumors develop spontaneously in LEC rats. 10) In the present study, we examined preneoplastic and neoplastic lesions of the kidneys in rats of 51-120 weeks old, and the changes in renal copper and iron concentrations of LEC and F344 rats of 6-106 weeks old. We also investigated the effect of D-penicillamine on spontaneous renal carcinogenesis. MATERIALS AND METHODSAnimals LEC/Tj rats and LEA/Tj rats, a sibling line of the LEC rats, were bred in the Institute for Animal Experimentation of the University of Tokushima, in specific pathogen-free conditions. In our laboratory, the mortality rate of LEC rats during the period of jaundice is 12.4% for males (n=193) and 42.3% for females (n=...

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Selective removal of copper accumulating in a form bound to metallothionein in the liver of LEC rats by tetrathiomolybdate

Suzuki¹

1997

J. Trace Elem. Exp. Med.

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Unusual Generation of Hydroxyl Radicals in Hepatic Copper-Metallothionein of LEC (Long-Evans Cinnamon) Rats in the Presence of Hydrogen Peroxide

Cited by 50 publications

References 0 publications

Evaluation of Distribution Patterns for Copper and Zinc in Metallothionein and Superoxide Dismutase in Chronic Liver Diseases and Hepatocellular Carcinoma Using High-Performance Liquid Chromatography (HPLC)

Evaluation of Distribution Patterns for Copper and Zinc in Metallothionein and Superoxide Dismutase in Chronic Liver Diseases and Hepatocellular Carcinoma Using High-Performance Liquid Chromatography (HPLC)

Role of Copper Accumulation in Spontaneous Renal Carcinogenesis in Long‐Evans Cinnamon Rats

Selective removal of copper accumulating in a form bound to metallothionein in the liver of LEC rats by tetrathiomolybdate

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