Low Susceptibility of Long‐Evans Cinnamon Rats to N‐Butyl‐N‐(4‐hydroxybutyl)‐nitrosamine‐induced Urinary Bladder Carcinogenesis and Inhibitory Effect of Urinary Copper

Chone, Yoshifumi; Kinouchi, Takemi; T, Yamada; Suzuki, Yasuo; Kitaura, Keisuke; Jiao, Zhongxian; Minami, Takanori; Bando, Yoshimi; Uehara, Hisanori; Mochizuki, Masahito; Ohnishi, Yoshinari; Izumi, Kiyotaka

doi:10.1111/j.1349-7006.2000.tb00855.x

Cited by 3 publications

(4 citation statements)

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“…In a recent carcinogenicity study, we found that LEC rats were more resistant to BBN-induced bladder carcinogenesis than F344 or Long-Evans Agouti rats. 24) Therefore, LEC rats are not necessarily a carcinogen-susceptible strain. In the present study, LEC rats were resistant to DEN-induced lung carcinogenesis, and WKAH.C-Atp7b and WKAH rats were susceptible.…”

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%

“…24) Therefore, LEC rats are not necessarily a carcinogen-susceptible strain. In the present study, LEC rats were resistant to DEN-induced lung carcinogenesis, and WKAH.C-Atp7b and WKAH rats were susceptible.…”

Section: Discussionmentioning

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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“…our studies (6,7). Prenatal and neonatal administrations of N -ethyl-N -nitrosourea (ENU) induce brain and trigeminal nerve tumors (8).…”

Section: Low Susceptibility To N -Ethyl-n -Nitrosourea-induced Transpmentioning

confidence: 98%

Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats

et al. 2009

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The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson's disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O(6)-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats.

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“…The difference in hepatocarcinogenic activity may not be explained with reference to metabolic potential, since there are no apparent differences in the urinary excretion of BCPN among the 4 rat strains (Wistar, ACI/N, SD and NAR) 23 . It was earlier reported that Long-Evans Cinnamon (LEC) rats, when compared to F344 rats, showed high susceptibility to liver carcinogenesis initiated/induced by BBN, related to marked liver lesions which occur because of a genetical alteration 24 . We have described lack of variation in susceptibility of F344 and WS (a Wistar-derived strain) rats to BBN-induced liver carcinogenesis 10 , in line with the finding that F344 and Wistar rats exhibit the same degree of susceptibility to initiation by diethylnitrosamine 25 .…”

Section: Discussionmentioning

confidence: 99%

Influence of Strain and Diet on Hepatocarcinogenicity of N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in Rats: Slight Inhibition of Preneoplastic Liver Lesion Development by Uracil

Hagiwara¹,

Mizutani

Miyata³

et al. 2005

J Toxicol Pathol

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Abstract:To assess sensitivity to hepatocarcinogenesis by BBN, formalin-fixed and paraffin-embedded rat liver tissues from two initiation/promotion (I/P) bioassays for urinary bladder carcinogenesis were sectioned, immunohistochemically stained for glutathione S-transferase placental form (GST-P), and quantitatively analyzed. In Experiment 1, male Sprague-Dawley (SD)/cShi strain rats (highly sensitive to urinary bladder carcinogenesis by BBN) and SD/gShi rats (insensitive), were treated with 0.05% BBN in the drinking water for 4 weeks and then housed for up to week 36, with or without exposure to bladder tumor promoters. Slightly higher quantitative values for small GST-P positive (GST-P + ) foci were found in SD/gShi rats (8.57/cm 2 ) compared to SD/cShi rats (2.48/cm 2 ). In Experiment 2, F344 and Lewis rats, subjected to a similar I/P protocol, were maintained on MF or CA-1 diet for 36 weeks. Higher quantitative values of GST-P + hepatocytic foci (more than 0.1 mm in diameter) were found in Lewis rats (9.51/cm 2 for MF diet; 7.95/cm 2 for CA-1 diet) compared to F344 rats (2.82/cm 2 and 1.30/cm 2 , respectively). Slight inhibiting effects of GST-P + foci were apparent in rats receiving uracil, but not sodium L-ascorbate, in the present experiment. Thus, it was confirmed that the bladder carcinogen BBN also targets the liver. The results, from quantitative analysis of small GST-P + foci as end-point marker lesions, indicate considerable strain differences, but that liver tumor modifying potential of test chemicals can be evaluated in I/P protocols for urinary bladder carcinogenesis using any strain of rat. (J Toxicol Pathol 2005; 18: 105-110)

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Low Susceptibility of Long‐Evans Cinnamon Rats to N‐Butyl‐N‐(4‐hydroxybutyl)‐nitrosamine‐induced Urinary Bladder Carcinogenesis and Inhibitory Effect of Urinary Copper

Cited by 3 publications

References 29 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

Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats

Influence of Strain and Diet on Hepatocarcinogenicity of N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in Rats: Slight Inhibition of Preneoplastic Liver Lesion Development by Uracil

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