| Project/Area Number |
61480432
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Tokyo College of Pharmacy |
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Principal Investigator |
WATABE Tadashi Professor Faculty of Pharmaceutical Sciences, Tokyo College of Pharmacy, 薬学部, 教授 (00057316)
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| Co-Investigator(Kenkyū-buntansha) |
OKUDA Haruhiro Research Faculty of Pharmaceutical Sciences, Tokyo College of Pharmacy, 薬学部, 助手 (30160807)
HIRATSUKA Akira Assistan Faculty of Pharmaceutical Sciences, Tokyo College of Pharmacy, 薬学部, 講師 (20165179)
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| Project Period (FY) |
1986 – 1988
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| Project Status |
Completed (Fiscal Year 1988)
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| Budget Amount *help |
¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 1988: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1987: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 1986: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Active oxygen / Microsomal lipid peroxidation / Fatty acid hydroperoxide / Epoxide / Glutathione peroxidase / Leukotriene A_4 / エポキシドヒドロラーゼ / 肝ミクロゾーム脂質過酸化 / 活性酸素 / 肝小胞体膜リン脂質 / パーオキシラジカル / 変異原性エポキシド / 脂質過酸化 / 抗酸化剤 / 肝ミクロゾームの脂質過酸化 / 脂質過酸化物 / 脂質パーオキシラジカル / 膜脂質アラキドン酸 / ジヒドロベンゾ〔a〕ピレン / アフラトキシン【B_1】 |
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| Research Abstract |
Endoplasmic reticulum of the mammalian hepatic cells has the largest area among cell organelle membranes and one of the most important sites for the lipid peroxidation (LPO) reaction. 5,16-Androstadien-3 -ol (ANDO) underwent oxidation by LPO of microsomes (Ms), derived from the endoplasmic reticulum, in the presence of ADP-Fe(III)-NADPH to afford ANDO 5,6- and 16,17-epoxides. The 5,6-epoxides were yielded only by LPO of Ms but not by cytochromes P-450. The microsomal cytochromes, however, epoxidized at the C_<16>-double bond of ANDO. The epoxidation of ANDO in LPO-induced Ms was performed by the action of hydroperoxy-radicals of polyunsaturated fatty acid residues (PUFA-OO ) of microsomal phospholipids. ANDO was an ideal substrate for estimating net contributions of LPO and cytochromes P-450 in microsomal oxidation of a chemical although it is very difficult to differentiate them with most of chemicals other than ANDO.
Glutathione (GSH) markedly reduced the LPO reaction occurring in Ms. A new type of GSH peroxidase was found in and isolated from liver Ms as a homogeneous protein with a molecular weight of 1.5 KD. The enzyme reduced hydroperoxides of microsomal phospholipids and a variety of PUF-//H with formation of oxidized GSH, but did not catalyze reduction of hydrogen peroxide. The enzyme was suggested to play an important role in scavenging hydroperoxides of microsomal phospholipids formed by LPO.
The highly physiologically active compounds leukotrienes A_4 (LTA_4), derived from arachidonate hydroperoxides, were inactivated by a new type of epoxide hydrolase (EH) of guinea pig liver cytosol. The EH, purified from the cytosol, hydrolyzed and detoxified xenobiotic di-substituted ethylene oxides.
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