| Project/Area Number |
03670140
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Akita University (1992)
Osaka University (1991) |
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Principal Investigator |
SUGIYAMA Toshihiro 1st Department of Biochemistry, Akita University School of Medicine, 医学部, 教授 (00127242)
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| Co-Investigator(Kenkyū-buntansha) |
FIJII Junichi Department of Biochemistry, Osaka University Medical School, 医学部, 講師 (00222258)
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| Project Period (FY) |
1991 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1992: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1991: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | DNA hypomethylation / spontaneous hepatitis / hepatoma / LEC rat / drug metabolism / choline-deficient diet / Cytochrome P450 / Wilson's disease / Sーアデノシルメチオニン合成酵素 / グルタチオン / 肝細胞分画 / 肝炎モデル / 肝癌自然発症 / ウイルソン病 |
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| Research Abstract |
Marked alterations of hepatic drug-metabolizing enzymes were observed in hepatitis- and hepatoma-predisposed rats (LEC rats) fed a choline-deficient diet. The diet enhanced the development of hepatitis with severe jaundice.
Cytochrome P-450 in hepatic microsomes from LEC and LEA rats fed a choline-deficient diet has reduced capacity to catalyze the oxidation of pentoxyresorufin rather than ethoxyresorufin. Similar selective changes in other mixed function oxidase activities may occur in the spontaneous hepatic carcinogenesis of LEC rats. The great difference in the cytochrome P-450_<PB> content of liver microsomes between LEC and LEA rats and the maintained constitutive levels of hepatic cytochrome P-450_<MC> in the LEC rats at 4 weeks and 3 months of age had been previously shown. The choline-deficient diet caused marked decreases of the levels of two major classes of cytochrome P-450, P-450_<PB> and P-450_<MC>. GST-Yp was dramatically increased, whereas GST-Ya, Yb1, and Yb2 were decreased. LEC rats mimic LEA rats (the control rats to LEC) fed a choline-deficient diet in terms of the above enzyme alterations. The enzyme changes in LEC rats treated with ethionine are also similar to those observed in LEA rats fed a choline-deficient diet. These results suggest that LEC rats have some defects in methyl-group metabolism, including DNA hypomethylation. It is likely that hypomethylation is involved in the pathogenesis of hepatitis and hepatoma in LEC rats. Such hypomethylation may initiate the hepatocytes that spontaneously develop hepatitis and hepatoma.
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