Effects of <scp>d</scp>‐Galactosamine Hydrochloride and Partial Hepatectomy on Spontaneous Hepatic Injury and Hepatocarcinogenesis in Long‐Evans Cinnamon Rats

Jiao, Zhongxian; Ohnishi, Takamasa; Bando, Yoshimi; Chone, Yoshifumi; Kitaura, Keisuke; Uehara, Hisanori; Suzuki, Yasuo; Nakamura, Toshikazu; Izumi, Kiyotaka

doi:10.1111/j.1349-7006.1999.tb00775.x

Cited by 2 publications

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References 31 publications

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“…This may have been due to hepatocyte renewal after a necrogenic dose of DEN, as was observed on repeated s.c. injections of D-galactosamine hydrochloride, a hepatotoxic agent, into LEC rats, and on partial hepatectomy in our recent study. 4) In the case of partial hepatectomy, the hepatic copper concentration of male LEC rats was 45% of that of sham-operated rats on day 14 and none of the rats died of hepatic injury. …”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…[1][2][3] About 10-20% of male, and 40-50% of female rats die of fulminant hepatitis. [2][3][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.…”

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confidence: 99%

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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Prevention of lethal hepatic injury in Long-Evans Cinnamon (LEC) rats by D-galactosamine hydrochloride

et al. 2006

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: Repeated injections of D-galactosamine hydrochloride (GalN) increase the survival rate of Long-Evans Cinnamon (LEC) rats, an animal model of Wilson's disease. The aim of the present study was to investigate the mechanism of GalN for prevention of spontaneous lethal hepatic injury in LEC rats. Male LEC rats were given a single subcutaneous injection of 300 mg/kg of GalN or vehicle (0.9% NaCl) at 14 weeks, and killed at 28 weeks of age. Next, 6-week-old male LEC rats were given weekly subcutaneous injections of 300 mg/kg of GalN or vehicle for 3 or 12 weeks, and their hepatic 8-hydroxydeoxy-2'-guanosine (8-OHdG), glutathione peroxidase (GPX), and catalase activities were measured. None of GalN-treated rats died of hepatic injury (0/12), whereas the mortality rate of control rats given 0.9% NaCl was 17% (2/12). GalN administration for 12 weeks decreased the hepatic 8-OHdG, and GalN administration for either 3 or 12 weeks increased the glutathione peroxidase activity. GalN administration increased the serum level of alanine aminotransferase, and accelerated megalocytic degeneration of the hepatocytes. GalN treatment is effective in preventing lethal hepatitis in LEC rats and decrease of oxidative DNA damage by GalN plays an important role in increase of the survival rate. 53:81-86, February, 2006

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Effects of d‐Galactosamine Hydrochloride and Partial Hepatectomy on Spontaneous Hepatic Injury and Hepatocarcinogenesis in Long‐Evans Cinnamon Rats

Cited by 2 publications

References 31 publications

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

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

Prevention of lethal hepatic injury in Long-Evans Cinnamon (LEC) rats by D-galactosamine hydrochloride

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