High copper and iron levels and expression of Mn-superoxide dismutase in mutant rats displaying hereditary hepatitis and hepatoma (LEC rats)

Suzuki, Keiichiro; Miyazawa, Nobuko; Nakata, Toshiyuki; Seo, Han Geuk; Sugiyama, Toshihiro; Taniguchi, Naoyuki

doi:10.1093/carcin/14.9.1881

Cited by 39 publications

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“…This level, however, is not so high when compared to a copper accumulation that is 40-60 times higher in LEC rat liver, as compared to the Fisher rat liver as a control [7]. In contrast, levels of manganese in LEC rat liver are < 1 ⁄10 levels of Wistar rat liver [6]. These contrary changes may have an influence on levels of Cu, Zn-, and Mn-superoxide dismutases (SODs), which require metal ions as integral cofactors for enzymatic activities.…”

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confidence: 69%

“…Abnormal hepatic iron accumulation is also observed in LEC rats [5,6]. Levels of iron concentrations in the liver of 18-week-old LEC rats reached up to three times those found in Wistar rat livers of the same age [6]. This level, however, is not so high when compared to a copper accumulation that is 40-60 times higher in LEC rat liver, as compared to the Fisher rat liver as a control [7].…”

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confidence: 76%

“…Thus other abnormalities may be present during hepatocarcinogenesis in LEC rats. Abnormal hepatic iron accumulation is also observed in LEC rats [5,6]. Levels of iron concentrations in the liver of 18-week-old LEC rats reached up to three times those found in Wistar rat livers of the same age [6].…”

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confidence: 79%

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LEC rats: An overview of recent findings

Miyoshi

Fujii

Hayashi

et al. 1997

J. Trace Elem. Exp. Med.

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confidence: 69%

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confidence: 76%

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LEC rats: An overview of recent findings

Miyoshi

Fujii

Hayashi

et al. 1997

J. Trace Elem. Exp. Med.

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“…[27][28][29] The amount of 8-OHdG in DNA is increased in the liver and kidney of LEC rats, 30) and the levels of Cu,Zn-superoxide dismutase, a specific scavenger of superoxide, in LEC rats are lower than those in Wistar rats, especially in the liver and kidney. 31) Copper and/or hemolysis-induced iron accumulation are considered to play roles in hepatocarcinogenesis in LEC rats, because copper-induced hemolysis occurs in the period of necrotizing hepatitis, and iron-deficient diet prevents the development of liver tumors. 32,33) In the present study, despite the diffuse periportal hemosiderosis of hepatocytes (data not shown) and the increased hepatic iron concentration the incidence of hepatocellular tumors in D-penicillamine-treated LEC rats was lower than that in controls, although we did not measure metal concentrations during the period of jaundice.…”

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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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“…The Sod2 gene encodes an intramitochondrial free radical scavenging Mn-enzyme that is the first line of defense against superoxide produced as a toxic by-product of oxidative phosphorylation [3]. In this terms, it should be noted that the Mn-SOD levels in the LEC rat are lower than those of the normal control, especially in the liver and kidney [22], and that the amount of 8-hydroxydeoxyguanosine in DNA, a marker of active oxygen-derived DNA damage, is increased in the liver and kidney of the LEC rat [27]. These informations will help us to apply a positional candidate gene approach to clarify whether these genes are involved in the pathogenesis of renal cell carcinoma in the LEC rat.…”

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Identification of a Locus for Susceptibility to Renal Cell Carcinoma in the Long-Evans Cinnamon Rat

Wei

Izumi

Hino

et al. 1999

The Journal of Veterinary Medical Science

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ABSTRACT. The Long-Evans Cinnamon (LEC) mutant rat shows higher incidence of renal cell carcinomas induced by a treatment with the chemical carcinogen N-diethylnitrosamine, as compared to the normal control rat. We performed the first genome-wide scan for genes responsible for susceptibility to chemically induced renal cell carcinoma in an F 2 intercross obtained by mating the LEC and Fischer-344 (F344) rats. The genotype of 71 (F344 × LEC) F 2 progenies was determined with the use of 338 simple sequence length polymorphisms (SSLPs) spread over the genome. The F 2 rats which carried renal cell carcinoma were shown to possess the incidence of homozygosity of the LEC allele which is higher than that of the other genotypes at SSLP markers on chromosome 5 (χ 2 = 17.5 for D5Rat21). Our linkage analysis has led to the revelation of a novel gene that influences susceptibility to renal cell carcinoma on rat chromosome 5.-KEY WORDS: LEC rat, linkage, renal cell carcinoma.

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High copper and iron levels and expression of Mn-superoxide dismutase in mutant rats displaying hereditary hepatitis and hepatoma (LEC rats)

Cited by 39 publications

References 0 publications

LEC rats: An overview of recent findings

LEC rats: An overview of recent findings

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

Identification of a Locus for Susceptibility to Renal Cell Carcinoma in the Long-Evans Cinnamon Rat

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