肝細胞癌症例における銅蓄積の意義
1. はじめに 生体内微量元素の過不足は各種の代謝異常や疾患を引き起こす. 特に, 生体内代謝の主要臓器である肝臓は微量金属の代謝においても主役を果たしており, 銅, 鉄の過剰を原因としたウイルソン病, ヘモクロマトーシスといった疾患が知られている1,2). また, 肝性脳症における亜鉛の関与2), 慢性肝疾患や肝細胞癌における微量金属との関連についても報告がみられる4-12). 我々は高感度で多元素を同時にmg単位の試料中の微量金属含量が検出できるPIXE(Particle Induced X-Ray Emission)法13)を慢性肝疾患に応用し, 金属含有量と慢性肝疾患の進行及び発癌との...
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| Published in | BIOMEDICAL RESEARCH ON TRACE ELEMENTS Vol. 16; no. 1; pp. 25 - 31 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本微量元素学会
2005
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| Online Access | Get full text |
| ISSN | 0916-717X 1880-1404 |
| DOI | 10.11299/brte.16.25 |
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| Abstract | 1. はじめに 生体内微量元素の過不足は各種の代謝異常や疾患を引き起こす. 特に, 生体内代謝の主要臓器である肝臓は微量金属の代謝においても主役を果たしており, 銅, 鉄の過剰を原因としたウイルソン病, ヘモクロマトーシスといった疾患が知られている1,2). また, 肝性脳症における亜鉛の関与2), 慢性肝疾患や肝細胞癌における微量金属との関連についても報告がみられる4-12). 我々は高感度で多元素を同時にmg単位の試料中の微量金属含量が検出できるPIXE(Particle Induced X-Ray Emission)法13)を慢性肝疾患に応用し, 金属含有量と慢性肝疾患の進行及び発癌との関連について検討した. 2. 肝細胞癌における磁気共鳴画像(MRI)の信号強度と病理所見との関連 MRIは肝細胞癌の診断に広く行われており, 特徴的所見よりその確定診断に有用である. すなわち, 小肝細胞癌(腫瘍径3cm以下)ではT1強調像において高信号を呈することが特徴的であり, 60％前後がT1強調像において高信号を呈する. 肝細胞癌でT1強調像において高信号を呈する原因として, 我々は腫瘍内の脂肪変性14), および腫瘍内の銅蓄積の関与を報告した10). さらに, 小肝細胞癌および非癌部肝実質の微量金属含量とMRIの信号強度パターンとの関連について検討した15). |
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| AbstractList | 1. はじめに 生体内微量元素の過不足は各種の代謝異常や疾患を引き起こす. 特に, 生体内代謝の主要臓器である肝臓は微量金属の代謝においても主役を果たしており, 銅, 鉄の過剰を原因としたウイルソン病, ヘモクロマトーシスといった疾患が知られている1,2). また, 肝性脳症における亜鉛の関与2), 慢性肝疾患や肝細胞癌における微量金属との関連についても報告がみられる4-12). 我々は高感度で多元素を同時にmg単位の試料中の微量金属含量が検出できるPIXE(Particle Induced X-Ray Emission)法13)を慢性肝疾患に応用し, 金属含有量と慢性肝疾患の進行及び発癌との関連について検討した. 2. 肝細胞癌における磁気共鳴画像(MRI)の信号強度と病理所見との関連 MRIは肝細胞癌の診断に広く行われており, 特徴的所見よりその確定診断に有用である. すなわち, 小肝細胞癌(腫瘍径3cm以下)ではT1強調像において高信号を呈することが特徴的であり, 60％前後がT1強調像において高信号を呈する. 肝細胞癌でT1強調像において高信号を呈する原因として, 我々は腫瘍内の脂肪変性14), および腫瘍内の銅蓄積の関与を報告した10). さらに, 小肝細胞癌および非癌部肝実質の微量金属含量とMRIの信号強度パターンとの関連について検討した15). |
| Author | 湯川, 雅枝 税所, 宏光 伊古田, 暢夫 吉川, 正治 岡部, 真一郎 福田, 浩之 江原, 正明 |
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| DOI | 10.11299/brte.16.25 |
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| References | 11) Tashiro-Itoh T, Ichida T, Matsuda Y, Satoh T, Sugiyama M, Tanaka Y, Ichikawa T, Itoh S, Nomoto M, Asakura H. Metallothionein expression and concentrations of copper and zinc are associated with tumor differentiation in hepatocellular carcinoma. Liver 17, 300-306, 1997 20) Ebara M, Fukuda H, Hatano R, Yoshikawa M, Sugiura N, Saisho H, Kondo F, Yukawa M. Metal contents in the liver of patients with chronic liver disease caused by hepatitis C virus. Oncology 65: 323-330, 2003. 22) Cerutti PA. Prooxidant states and tumor promotion. Science 227, 375-381, 1985. 5) Nagase N, Korno H, Chang YC, Nakamura T. Iron, copper and zinc levels in serum and cirrhotic liver of patients with and without hepatocellular carcinoma. Oncology 46, 293-296, 1989 29) Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, and Kasai H. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res., 54, 3171-3172, 1994. 23) Liaw KY, Lee PH, Wu FC, Tsai JS, Lin-Shiau SY. Zinc, Copper, and superoxide dismutase in hepatocellular carcinoma. Am. J. Gastroenterol. 92, 2260-2263, 1997. 3) Van der Rijt CCD, Schalm SW, Schat H, Foeken K, Jong GD. Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 100, 1114-1118, 1991 13) Khaliquzzaman M, Zaman MB, Khan AH. Trace element analysis in biological materials by external beam PIXE. Nucl Instrum Meth 181, 209-215, 1981. 15) Ebara M, Fukuda H, Kojima Y, Morimoto N, Yoshikawa M, Sugiura N, Satoh T, Kondo F, Yukawa M, Matsumoto T, Saisho H. Small hepatocellular carcinoma: ralationship of signal intensity to histologic findings and metal content of the tumor and surrounding hepatic parenchyma. Radiology 210, 81-88, 1999. 17) Mills PR, Fell GS, Bessent RG, Nelson LM, Russell RI. A study of zinc metabolism in alcoholic cirrhosis. Clin Sci 64, 527-535, 1983. 18) Bonkovsky HL, Ponka P, Bacon BR, Drysdale J, Grace ND, Tavill AS. An update on iron metabolism: summary of the fifith international conference on disorders of iron metabolism. Hepatology 24, 718-729, 1996. 14) Ebara M, Ohto M, Watanabe Y, et al. Diagnosis of small hepatocellular carcinoma: correlation of MR imaging and histologic studies. Radiology 159, 371-377, 1986. 7) Deugnier YM, Guyader D, Crantock L, Lopez JM, Turlin B, Yaouanq J, Jouanolle H, Campion JP, Launois B, Halliday JW, Powell LW, Brissot P. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology 104, 228-234, 1993 24) Sakurai H, Nakajima K, Kamada H, Satoh H, Otaki N., Kimura M, Kawano K, and Hagino T. Copper-metallothionein distribution in the liver of Long-Evans Cinnamon rats: Studies on immunohistochemical staining, metal determination, gel filtration and electron spin resonance spectroscopy. Biochem. Biophys. Res. Commun., 192, 893-898, 1993. 32) Jong-Hon K, Togashi Y, Kasai H, Hosokawa M, and Takeichi N. Prevention of spontaneous hepatocellular carcinoma in Long-Evans Cinnamon rats with hereditary hepatitis by administration of D-penicillamine. Hepatology, 18, 614-620, 1993. 26) Sakurai H, Satoh H, Hatanaka A, Sawada T, Kawano K, Hagino T, and Nakajima K. Unusual generation of hydroxyl radicals in hepatic copper-metallothionein of LEC (Long-Evans Cinnamon) rats in the presence of hydrogen peroxide. Biochem. Biophys. Res. Commun., 199, 313-318, 1994. 30) Sasaki N, Hayashizaki Y, Muramatsu M, Matsuda Y, Ando Y, Kuramoto T, Serikawa T, Azuma T, Naito A, Agui T, Yamashita T, Miyoshi I, Takeichi N, and Kasai N. The gene responsible for LEC hepatitis, located on rat chromosome 16, is the homolog to the human Wilson disease gene. Biochem. Biophys. Res. Commun., 202, 512-518, 1994. 12) Hatano R, Ebara M, Fukuda H, Yoshikawa M, Sugiura N, Kondo F, Yukawa M, Saisho H. Accumulation of copper in the liver and hepatic injury in chronic hepatitis C. J. Gsatroenterol. Hepatol 1, 786-791, 2000. 10) Ebara M, Wtatanabe S, Kita K, Yoshikawa M, Sugiura N, Ohto M, Kondo F, Kondo Y. MR Imaging of small hepatocellular carcinoma: effect of intratumoral copper content on signal intensity. Radiology 180, 617-621, 1991. 27) Thomas JP, Bachowski GJ, and Girotti AW. Inhibition of cell membrane lipid peroxidatin by cadmium- and zinc-metallothioneins. Biochem. Biophys. Acta, 884, 448-461, 1986 19) Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated process? Hepatology 11, 127-137, 1990. 2) Sternlieb I. Copper and the liver. Gastroenterology 78, 1615-1628, 1980 8) Haratake J, Horie A, Nakashima A, Takeda S, Mori A. Minute hepatoma with excessive copper accumulation. Arch Pathol Lab Med 110, 192-194, 1986 21) Oikawa S, Kurasaki M, Kojima Y, Kawanishi S. Oxidative and nonoxidative mechanisms of site-specific DNA cleavage induced by copper-containing metallothioneins. Biochemistry(US) 34, 8763-8770, 1995 33) Sone H, Maeda M, Wakabayashi K, Takeichi N, Mori M, Sugimura T, and Nagao M. Inhibition of hereditary hepatitis and liver tumor development in Long-Evans Cinnamon rats by the copper-chelating agent trientine dihydrochloride. Hepatology, 23, 764-770, 1996. 28) Shibutani S, Takeshita M, and Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature, 349, 431-434, 1991. 6) Olynyk JK, Reddy R, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR. Hepatic iron concentration as a predictor of respnse to interferon alpha therapy in chronic hepatitis C. Gastroenterology 108, 1104-1109, 1995 4) Kew MC, Mallett RC. Hepatic zinc concentrations in primary cancer of the liver. Brit J Cancer 29, 80-83, 1974 1) Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 6, 24-29, 1986 9) Haratake J, Horie A, Takeda S. Histochemical and ultrastructural study of copper-binding protein in hepatocellular carcinoma. Cancer 60, 1369-1374, 1987. 16) Ebara M, Fukuda H, Hatano R, Saisho H, Nagato Y, Suzuki K, Nakajima K, Yukawa M, Kondo F, Nakayama A, Sakurai H. Relashioship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma. J. of Hepatology 33, 415-422, 2000. 25) Suzuki KT. Disorderd copper metabolism in LEC rat, an animal model of Wilson disease: role of metallothionein. Res. Commun. Mol. Phath. 89, 221-239, 1995. 31) Eagon PK, Teepe AG, Elm MS, Tadic SD, Epley MJ, Beiler BE, Shinozuka H, and Rao KN. Hepatic hyperplasia and cancer in rats: alterations in copper metabolism. Carcinogenesis, 20, 1091-1096, 1999. |
| References_xml | – reference: 9) Haratake J, Horie A, Takeda S. Histochemical and ultrastructural study of copper-binding protein in hepatocellular carcinoma. Cancer 60, 1369-1374, 1987. – reference: 3) Van der Rijt CCD, Schalm SW, Schat H, Foeken K, Jong GD. Overt hepatic encephalopathy precipitated by zinc deficiency. Gastroenterology 100, 1114-1118, 1991 – reference: 24) Sakurai H, Nakajima K, Kamada H, Satoh H, Otaki N., Kimura M, Kawano K, and Hagino T. Copper-metallothionein distribution in the liver of Long-Evans Cinnamon rats: Studies on immunohistochemical staining, metal determination, gel filtration and electron spin resonance spectroscopy. Biochem. Biophys. Res. Commun., 192, 893-898, 1993. – reference: 31) Eagon PK, Teepe AG, Elm MS, Tadic SD, Epley MJ, Beiler BE, Shinozuka H, and Rao KN. Hepatic hyperplasia and cancer in rats: alterations in copper metabolism. Carcinogenesis, 20, 1091-1096, 1999. – reference: 25) Suzuki KT. Disorderd copper metabolism in LEC rat, an animal model of Wilson disease: role of metallothionein. Res. Commun. Mol. Phath. 89, 221-239, 1995. – reference: 15) Ebara M, Fukuda H, Kojima Y, Morimoto N, Yoshikawa M, Sugiura N, Satoh T, Kondo F, Yukawa M, Matsumoto T, Saisho H. Small hepatocellular carcinoma: ralationship of signal intensity to histologic findings and metal content of the tumor and surrounding hepatic parenchyma. Radiology 210, 81-88, 1999. – reference: 7) Deugnier YM, Guyader D, Crantock L, Lopez JM, Turlin B, Yaouanq J, Jouanolle H, Campion JP, Launois B, Halliday JW, Powell LW, Brissot P. Primary liver cancer in genetic hemochromatosis: a clinical, pathological, and pathogenetic study of 54 cases. Gastroenterology 104, 228-234, 1993 – reference: 28) Shibutani S, Takeshita M, and Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature, 349, 431-434, 1991. – reference: 21) Oikawa S, Kurasaki M, Kojima Y, Kawanishi S. Oxidative and nonoxidative mechanisms of site-specific DNA cleavage induced by copper-containing metallothioneins. Biochemistry(US) 34, 8763-8770, 1995 – reference: 23) Liaw KY, Lee PH, Wu FC, Tsai JS, Lin-Shiau SY. Zinc, Copper, and superoxide dismutase in hepatocellular carcinoma. Am. J. Gastroenterol. 92, 2260-2263, 1997. – reference: 10) Ebara M, Wtatanabe S, Kita K, Yoshikawa M, Sugiura N, Ohto M, Kondo F, Kondo Y. MR Imaging of small hepatocellular carcinoma: effect of intratumoral copper content on signal intensity. Radiology 180, 617-621, 1991. – reference: 29) Shimoda R, Nagashima M, Sakamoto M, Yamaguchi N, Hirohashi S, Yokota J, and Kasai H. Increased formation of oxidative DNA damage, 8-hydroxydeoxyguanosine, in human livers with chronic hepatitis. Cancer Res., 54, 3171-3172, 1994. – reference: 19) Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated process? Hepatology 11, 127-137, 1990. – reference: 6) Olynyk JK, Reddy R, Di Bisceglie AM, Jeffers LJ, Parker TI, Radick JL, Schiff ER, Bacon BR. Hepatic iron concentration as a predictor of respnse to interferon alpha therapy in chronic hepatitis C. Gastroenterology 108, 1104-1109, 1995 – reference: 26) Sakurai H, Satoh H, Hatanaka A, Sawada T, Kawano K, Hagino T, and Nakajima K. Unusual generation of hydroxyl radicals in hepatic copper-metallothionein of LEC (Long-Evans Cinnamon) rats in the presence of hydrogen peroxide. Biochem. Biophys. Res. Commun., 199, 313-318, 1994. – reference: 13) Khaliquzzaman M, Zaman MB, Khan AH. Trace element analysis in biological materials by external beam PIXE. Nucl Instrum Meth 181, 209-215, 1981. – reference: 5) Nagase N, Korno H, Chang YC, Nakamura T. Iron, copper and zinc levels in serum and cirrhotic liver of patients with and without hepatocellular carcinoma. Oncology 46, 293-296, 1989 – reference: 22) Cerutti PA. Prooxidant states and tumor promotion. Science 227, 375-381, 1985. – reference: 1) Bassett ML, Halliday JW, Powell LW. Value of hepatic iron measurements in early hemochromatosis and determination of the critical iron level associated with fibrosis. Hepatology 6, 24-29, 1986 – reference: 2) Sternlieb I. Copper and the liver. Gastroenterology 78, 1615-1628, 1980 – reference: 33) Sone H, Maeda M, Wakabayashi K, Takeichi N, Mori M, Sugimura T, and Nagao M. Inhibition of hereditary hepatitis and liver tumor development in Long-Evans Cinnamon rats by the copper-chelating agent trientine dihydrochloride. Hepatology, 23, 764-770, 1996. – reference: 4) Kew MC, Mallett RC. Hepatic zinc concentrations in primary cancer of the liver. Brit J Cancer 29, 80-83, 1974 – reference: 32) Jong-Hon K, Togashi Y, Kasai H, Hosokawa M, and Takeichi N. Prevention of spontaneous hepatocellular carcinoma in Long-Evans Cinnamon rats with hereditary hepatitis by administration of D-penicillamine. Hepatology, 18, 614-620, 1993. – reference: 8) Haratake J, Horie A, Nakashima A, Takeda S, Mori A. Minute hepatoma with excessive copper accumulation. Arch Pathol Lab Med 110, 192-194, 1986 – reference: 18) Bonkovsky HL, Ponka P, Bacon BR, Drysdale J, Grace ND, Tavill AS. An update on iron metabolism: summary of the fifith international conference on disorders of iron metabolism. Hepatology 24, 718-729, 1996. – reference: 27) Thomas JP, Bachowski GJ, and Girotti AW. Inhibition of cell membrane lipid peroxidatin by cadmium- and zinc-metallothioneins. Biochem. Biophys. Acta, 884, 448-461, 1986 – reference: 30) Sasaki N, Hayashizaki Y, Muramatsu M, Matsuda Y, Ando Y, Kuramoto T, Serikawa T, Azuma T, Naito A, Agui T, Yamashita T, Miyoshi I, Takeichi N, and Kasai N. The gene responsible for LEC hepatitis, located on rat chromosome 16, is the homolog to the human Wilson disease gene. Biochem. Biophys. Res. Commun., 202, 512-518, 1994. – reference: 11) Tashiro-Itoh T, Ichida T, Matsuda Y, Satoh T, Sugiyama M, Tanaka Y, Ichikawa T, Itoh S, Nomoto M, Asakura H. Metallothionein expression and concentrations of copper and zinc are associated with tumor differentiation in hepatocellular carcinoma. Liver 17, 300-306, 1997 – reference: 12) Hatano R, Ebara M, Fukuda H, Yoshikawa M, Sugiura N, Kondo F, Yukawa M, Saisho H. Accumulation of copper in the liver and hepatic injury in chronic hepatitis C. J. Gsatroenterol. Hepatol 1, 786-791, 2000. – reference: 17) Mills PR, Fell GS, Bessent RG, Nelson LM, Russell RI. A study of zinc metabolism in alcoholic cirrhosis. Clin Sci 64, 527-535, 1983. – reference: 16) Ebara M, Fukuda H, Hatano R, Saisho H, Nagato Y, Suzuki K, Nakajima K, Yukawa M, Kondo F, Nakayama A, Sakurai H. Relashioship between copper, zinc and metallothionein in hepatocellular carcinoma and its surrounding liver parenchyma. J. of Hepatology 33, 415-422, 2000. – reference: 14) Ebara M, Ohto M, Watanabe Y, et al. Diagnosis of small hepatocellular carcinoma: correlation of MR imaging and histologic studies. Radiology 159, 371-377, 1986. – reference: 20) Ebara M, Fukuda H, Hatano R, Yoshikawa M, Sugiura N, Saisho H, Kondo F, Yukawa M. Metal contents in the liver of patients with chronic liver disease caused by hepatitis C virus. Oncology 65: 323-330, 2003. |
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