1997 Fiscal Year Final Research Report Summary
Contribution of glutathione to multidrug resistance and the its regulation with active oxygen modulators
| Project/Area Number |
08672521
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Gifu Pharmaceutical University |
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Principal Investigator |
ADACHI Tetsuo Gifu Pharm.Univ./Dept.of Pharm./Associate Professor, 薬学部, 助教授 (40137063)
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| Co-Investigator(Kenkyū-buntansha) |
HIRANO Kazuyuki Gifu Pharm.Univ./Dept.of Pharm./Professor, 薬学部, 教授 (90057365)
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| Project Period (FY) |
1996 – 1997
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| Keywords | Glutathione / Multidrug resistance-associated protein / Active oxygen / Superoxide dismutase / Glucuronosyl conjugate |
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| Research Abstract |
Multidrug resistance-associated protein (MRP) has shown to transport glutathione S-conjugate. The effect of glutathione (GSH) on the transport of glucuronosyl etoposide, a major metabolite of etoposide in MRP overexpressing cell line KB/VP-4.
1.The involvement of MRP in the transport of drug conjugates was investigated using membrane vesicles prepared from KB/VP-4 cells. The ATP-dependent transport of not only GSH-conjugate such as [^3H]-leukotriene C4, but also glucuronosyl conjugate of [^3H] etoposide. This result demonstrates that MRP is a pump with a broad specificity.
2.The butionine sulfoximine (BSO)-exposure reduced the GSH level inKB/VP-4 cells. The efflux of glucuronosyl etoposide was5-times faster from KB/VP-4 than from KB cells (wild type cells). BSO abolished the increased efflux of drug from KB/VP-4.
3.In KB/VP-4 cells, the contents of copper, zinc-superoxide dismutase and manganese-superoxide dismutase were 1.5-fold and 6-fold higher than those in KB cells, respectively. This result shows that KB/VP-4 cell might to be more resistant to active oxygens.
4.Molecular genetic studies of extracellular-superoxide dismutase have shown that a single base substitution generating the exchange of glycine for arginine 213 causes the impairment of its binding ability to endothelial cell surface and susceptibility to trypsin-like proteinases. The binding of EC-SOD to cell surface is an especially efficient way of protecting cells against external superoxide anion. The decrease of the protective capacity on the endothelial surface by EC-SOD might accelerate the renal, cardiovascular dysfunctions, diabetes and hyperlipidemia.
The change of SOD isozyme might affect on the ATP-dependent export of drug which are controlled by active oxygen modulators such as GSH.
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[Publications] Harutaka Yamada, Yasukazu Yamada, Tetsuo Adachi, Haruko Goto, Nobuaki Ogasawara, Arao Futenma, Mitsuru Kitano, Hironobu Miyai, Atsushi Fukatsu, Kazuyuki Hirano, Shinichi Kakumu: "Polymorphism of extracellular superoxide dismutase (EC-SOD) gene : Relation to the mutation responsible for high EC-SOD level in serum." Jpn.J.Human Genet.42. 353-356 (1997)
Description
「研究成果報告書概要(欧文)」より
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