Unusual accumulation of copper related to induction of metallothionein in the liver of LEC rats

Fukudome, Akihito; Tawa, Riichi; Kito, Masahiro; Takeshima, Shigeo; Kimura, Masaki; Otaki, Noriko; Nakajima, Katsuyuki; Hagino, T.; Kawano, Kazuya; Hirai, Shoji; Suzuki, Satoshi

doi:10.1016/s0006-291x(05)80037-3

Cited by 38 publications

(21 citation statements)

References 8 publications

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“…16) Tashiro-Itoh et al employed an immunostaining technique and reported an increase in the Cu content and enhanced staining for MT in human HCC, especially in well-differentiated HCC.…”

Section: Discussionmentioning

confidence: 99%

“…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. They suggest the increased free radical produced by Cu-MT in hepatocyte may cause hepatic injury.…”

Section: Discussionmentioning

confidence: 99%

“…14) The levels of MT in tissue were determined by radioimmunoassay according to the method by Sakurai et al 16) The MT and SOD fractions within the HPLC fraction were determined using authentic samples.…”

Section: Subjectsmentioning

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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“…16) Tashiro-Itoh et al employed an immunostaining technique and reported an increase in the Cu content and enhanced staining for MT in human HCC, especially in well-differentiated HCC.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

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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“…Zinc concentration in the liver of LEC rats increased in a similar way to that of metallothionein, to which copper and zinc are known to bind, 21 is high. 22 Purified metallothionein-copper iron concentration up to the age of 14 weeks, but it decreased siginificantly in association with hepatitis complex from LEC rat liver has been shown to generate higher levels of active oxygen species than that purified development. This decrease in zinc level was suppressed by trientine administration.…”

Section: Discussionmentioning

confidence: 94%

Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride

et al. 1996

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long-term administration of the agent. The copper level Trientine dihydrochloride (trientine) is an alternative in the liver of treated rats was reduced by 33% at 87 medicinal copper chelating agent for patients with Wilweeks of age. Development of HCC in LEC rats might be son's disease of penicillamine intolerance. We examined partly, but not totally, because of copper accumulation. the effects of trientine on the spontaneous development No effects on the levels of copper, iron, or zinc in the of hepatitis and hepatic tumors, by its short-term and liver of LEA rats was detected, and no adverse effects long-term administration to Long-Evans cinnamon were detected in either LEC or LEA rats after both short-(LEC) rats with an accumulation of copper in the liver, and long-term administration of trientine in drinking as animal models of Wilson's disease. Male rats were water. (HEPATOLOGY 1996;23:764-770.) given trientine in their drinking water at 1500 ppm for 18 weeks, from 6 weeks to 24 weeks of age in short-term experiment, and 1500 ppm for 27 weeks then 750 ppmThe mutant strain of rats, LEC (Long-Evans cinnafor 52 weeks, from 8 to 87 weeks of age in the long-term mon) was first found after sudden death of a number experiment. Development of hepatitis was observed in the control LEC rats at 18 weeks of age. They had high of them at 18-20 weeks of age, following their developlevels of plasma transaminases (glutamic oxaloacetic ment of hepatitis. This strain of rats consistently develtransaminase [GOT], glutamic pyruvic transaminase ops hepatitis with varying degrees of severity. The hep-[GPT]), and on pathological examination, hepatocyte de-atitis is characterized by an increase in the serum struction was observed. Histological findings revealed levels of glutamic oxaloacetic transaminase (GOT) and that short-term administration of trientine inhibited the glutamic pyruvic transaminase (GPT), hyperbilirubidevelopment of hepatitis remarkably. The plasma GOT nemia, and massive necrosis without an inflammatory and GPT levels of treated animals were only slightly cells response. [1][2][3] Most of the rats surviving the hepati- In the long-term administration of trientine, the inci-accumulate copper in their livers. 5 By linkage analysis dence of hepatic cell carcinoma (HCC) in the treated rats of F 1 back-crosses, we found that the genetic trait leadwas 67% that of the untreated LEC rats, and the number ing to the accumulation of copper in the liver is tightly of HCCs per rat in the treated group was 0.7 { 0.5, being linked with development of hepatitis. 6 Linkage analysignificantly lower as compared with 4.7 { 3.5 in the sis of F 1 back-crosses has also suggested that the gene untreated rats. Additionally, the development of cholan-responsible for Wilson's disease (Wc1/pWD), which engiofibrosis in LEC rats was completely prevented by codes a copper transporting P-type ATPase (ATP7B), is a candidate gene for hepatitis development in LEC rats. 7,8 Actually, a deletion in the rat Atp7b was found. 9Abbreviations: LEC, Lon...

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“…Age-matched male and female Long-Evans Agouti (LEA) rats were [14,15,19,[21][22][23][24][28][29][30][31][32]. In this early stage several biochemical parameters related to hepatic dysfunction, such as the plasma aspartate transaminase and glutamic-pyruvic transaminase levels, are still within the normal ranges (data not shown [14,15,21,[33][34][35].…”

Section: Animalsmentioning

confidence: 99%

High Expression Of Atp7b MRNA In The Peripheral Blood Mononuclear Cells Of The Long-Evans Cinnamon Rats: An Animal Model Of Wilsons Disease

Nakayama

Katoh²,

Shimizu³

et al. 2013

Hereditary Genet

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The Long-Evans Cinnamon (LEC) rat is an animal model of Wilson's disease. The rat has a mutation in the copper (Cu)-transporting P-type ATPase (Atp7b) gene that is homologous to the human Wilson's disease gene, ATP7B. The LEC rat shows all of the biochemical features of the disease. In this study, we focused on the expression levels of mutant Atp7b mRNAs in the peripheral blood mononuclear cells (PBMCs) of the LEC rats. Using quantitative real-time polymerase chain reaction (quantitative RT-PCR), we analyzed the expression levels of Atp7b mRNAs in the PBMCs cells of both the LEC rats and Long-Evans Agouti (LEA) rats, the latter being utilized as a control for the LEC rat. At the ages of 5 and 8 weeks, the inductions of Atp7b mRNA were manifested in the PBMCs of both male and female LEC rats, while their levels in the livers were significantly lower than those of the LEA rats. These results suggest the diversity of cell-physiological and endocrinological Cu metabolisms between the PBMCs and the livers of the LEC rats. Our findings indicate the possibility of a novel Cu metabolism in the cardiovascular network that is concerned with Atp7b of the PBMCs.

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Unusual accumulation of copper related to induction of metallothionein in the liver of LEC rats

Cited by 38 publications

References 8 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)

Inhibition of hereditary hepatitis and liver tumor development in Long-Evans cinnamon rats by the copper-chelating agent trientine dihydrochloride

High Expression Of Atp7b MRNA In The Peripheral Blood Mononuclear Cells Of The Long-Evans Cinnamon Rats: An Animal Model Of Wilsons Disease

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