Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.

Kato, Junji; Kobune, Masayoshi; Kohgo, Yutaka; Sakata, Naoki; Hisai, Hiroyuki; Nakamura, Tokiko; Sakamaki, Sumio; Sawada, Norimasa; Niitsu, Yoshiro

doi:10.1172/jci118875

Cited by 138 publications

(79 citation statements)

References 32 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 57%

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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Section: Discussioncontrasting

confidence: 57%

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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“…However, excess iron is a risk for various cancers (12,14,15). For example, hepatocytes infected with hepatitis virus B or C accumulate iron through iron dysregulation by low hepcidin, and are frequently transformed to hepatocellular carcinoma (16). Indeed, iron reduction can lower the risk for hepatic cancer (17) and probably in other cancers (18).…”

Section: Introductionmentioning

confidence: 99%

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

Nagai

Okazaki

Chew

et al. 2013

Cancer Prevention Research

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Asbestos was used worldwide in huge quantities in the past century. However, because of the unexpected carcinogenicity to mesothelial cells with an extremely long incubation period, many countries face this long-lasting social problem. Mesothelioma is often diagnosed in an advanced stage, for which no effective therapeutic protocols are yet established. We previously reported on the basis of animal experiments that the major pathology in asbestos-induced mesothelial carcinogenesis is local iron overload. Here, we undertook to find an effective strategy to prevent, delay, or lower the malignant potential of mesothelioma during asbestos-induced carcinogenesis. We used intraperitoneal injections of crocidolite to rats. We carried out a 16-week study to seek the maximal-tolerated intervention for iron reduction via oral deferasirox administration or intensive phlebotomy. Splenic iron deposition was significantly decreased with either method, and we found that Perls' iron staining in spleen is a good indicator for iron reduction. We injected a total of 10 mg crocidolite at the age of six weeks, and the preventive measures were via repeated oral administration of 25 to 50 mg/kg/d deferasirox or weekly to bimonthly phlebotomy of 4 to 10 mL/kg/d. The animals were observed until 110 weeks. Deferasirox administration significantly increased the fraction of less malignant epithelioid subtype. Although we found a slightly prolonged survival in deferasirox-treated female rats, larger sample size and refinement of the current protocol are necessary to deduce the cancer-preventive effects of deferasirox. Still, our results suggest deferasirox serves as a potential preventive strategy in people already exposed to asbestos via iron reduction. Cancer Prev Res; 6(11); 1222-30. Ó2013 AACR.

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“…[20][21][22] Iron-deficient diet also inhibits the development of liver tumors. 23) These data suggest that tumor development in LEC rats is a later event caused by chronic copper and/or iron toxicity.…”

Section: Discussionmentioning

confidence: 87%

Role of Atp7b Gene in Spontaneous and N‐Diethylnitrosamine‐induced Carcinogenesis in a New Congenic Strain, WKAH.C‐Atp7b Rats

Minami¹,

Kaneda²,

Otsuka³

et al. 2001

Japanese Journal of Cancer Research

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To examine whether Long-Evans Cinnamon (LEC) rats, a mutant rat model of Wilson's disease, have a susceptibility gene(s) to hepatocarcinogenesis in addition to the causative gene, Atp7b, we established a new congenic strain, WKAH.C-Atp7b rats, in which the Atp7b gene of the LEC rats is inserted into the normal Wistar-King Aptekman Hokkaido (WKAH) background. Hepatocellular tumors developed spontaneously in both sexes of WKAH.C-Atp7b rats, their incidence being slightly lower than that in LEC rats. Incidences of spontaneous liver tumors in LEC, WKAH.CAtp7b and WKAH rats correlated with hepatic copper and iron concentrations. Medium-term liver bioassay showed that LEC rats were more susceptible to the induction of glutathione S-transferase placental form-positive preneoplastic foci than WKAH.C-Atp7b rats, and WKAH.C-Atp7b rats were more susceptible than WKAH rats. In an N-diethylnitrosamine (DEN)-induced long-term carcinogenicity study, 1) LEC rats were similarly or rather less susceptible to hepatocellular tumors than WKAH.C-Atp7b and WKAH rats, indicating that the progression of the preneoplastic foci to liver cancer in LEC rats was worse than that in WKAH.C-Atp7b and WKAH rats, 2) the incidences of kidney tumors in LEC and WKAH.C-Atp7b rats were higher than that in WKAH rats and high copper concentrations in the kidneys were observed in LEC and WKAH.C-Atp7b rats, 3) LEC rats were resistant to lung carcinogenesis. These data indicate that the susceptibility of LEC rats to liver and kidney carcinogenesis could be explained by Atp7b gene mutation and that the susceptibility to lung carcinogenesis is controlled by gene(s) other than Atp7b.Key words: LEC rat -Atp7b -Congenic -N-Diethylnitrosamine -Copper LEC rats were established as a mutant strain in which hepatitis (hepatocellular necrosis) with severe jaundice and liver tumors develop spontaneously.1-3) About 10-20% of male, and 40-50% of female rats die of fulminant hepatitis.2-4) Their hepatitis is controlled by a single recessive gene designated as Wnd (Atp7b), which is a coppertransporting ATPase gene homologous to the Wilson's disease gene, and LEC rats have a partial deletion of the Atp7b gene.5) The Atp7b gene was originally named the hts gene, and mapped on chromosome 16. 6) These rats also show arrest of maturation from CD4 + 8 + to CD4 + 8 − cells in the thymus, which is not linked to hepatitis genetically and the T-helper immunodeficiency (thid) gene is mapped on chromosome 1. 7,8) In LEC rats, hepatocellular and renal cell tumors develop due to excess copper and/or hemolysis-induced iron accumulation in the organs.9-11) An in vivo short-term assay study suggested that LEC rats are a DENsusceptible strain 12) and the susceptibility of this strain to hepatocarcinogens is genetically independent of copper accumulation in the liver. 13) We have been employing genetic linkage analysis to determine hepatocarcinogen susceptibility loci using a total of 139 DEN-treated (F344×LEC)F2 and (LEC×F344)F2 rats, but we have not yet found susceptibility loci (unpublis...

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Hepatic iron deprivation prevents spontaneous development of fulminant hepatitis and liver cancer in Long-Evans Cinnamon rats.

Cited by 138 publications

References 32 publications

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

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

Deferasirox Induces Mesenchymal–Epithelial Transition in Crocidolite-Induced Mesothelial Carcinogenesis in Rats

Role of Atp7b Gene in Spontaneous and N‐Diethylnitrosamine‐induced Carcinogenesis in a New Congenic Strain, WKAH.C‐Atp7b Rats

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