Contribution of glutathione to multidrug resistance and the its regulation with active oxygen modulators
Contribution of glutathione to multidrug resistance and the its regulation with active oxygen modulators
批准号:
08672521
负责人:
ADACHI Tetsuo
金额:
$0.77万
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (C)
财政年份:
1996
资助国家:
日本
项目状态:
已结题
起止时间:
1996 至 1997
中文摘要
多药耐药相关蛋白(MRP)已被证明转运谷胱甘肽S-结合物。谷胱甘肽(GSH)对多药耐药蛋白(MRP)高表达细胞株KB/VP-4.1中依托泊苷代谢产物葡萄糖醛酸依托泊苷转运的影响。ATP依赖性转运不仅包括[^3H]-白三烯C4等GSH结合物,还包括[^3H]依托泊苷的葡萄糖醛酸结合物。这一结果表明MRP是一个具有广泛特异性的泵。2.丁硫氨酸亚砜(BSO)暴露降低KB/VP-4细胞的GSH水平。葡萄糖醛酸基依托泊苷从KB/VP-4的流出比从KB细胞(野生型细胞)快5倍。3. KB/VP-4细胞中铜、锌、锰超氧化物歧化酶含量分别是KB细胞的1.5倍和6倍。4.细胞外超氧化物歧化酶的分子遗传学研究表明,细胞外超氧化物歧化酶与内皮细胞表面结合能力降低,对胰蛋白酶样蛋白酶的敏感性降低。EC-SOD与细胞表面的结合是保护细胞免受外部超氧阴离子的特别有效的方式。EC-SOD对内皮细胞表面保护能力的降低可能会加速肾功能、心血管功能障碍、糖尿病和高脂血症的发生,SOD同工酶的改变可能会影响由GSH等活性氧调节剂控制的ATP依赖性药物输出。
英文摘要
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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Harutaka Yamada: "Polymorphism of extracellular superoxide dismutase (EC-SOD) gene:Relation to the mutation responsible for high EC-SOD level in serum" Japanese Journal of Human Genetics. 42. 353-356 (1997)
Harutaka Yamada:“细胞外超氧化物歧化酶 (EC-SOD) 基因的多态性:与血清中高 EC-SOD 水平的突变的关系”《日本人类遗传学杂志》。
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通讯作者:
Harutaka Yamada, Mitsuru Kitano, Atsushi Fukatsu, Mintan Son, Arao Futenma, Shinichi Kakumu, Yasukazu Yamada, Tetsuo Adachi, Kazuyuki Hirano: "Moleccular analysis of extracellular-superoxide dismutase in patients with chronic renal failure." Kidney and Fr
Harutaka Yamada、Mitsuru Kitano、Atsushi Fukatsu、Mintan Son、Arao Futenma、Shinichi Kakumu、Yasukazu Yamada、Tetsuo Adachi、Kazuyuki Hirano:“慢性肾功能衰竭患者细胞外超氧化物歧化酶的分子分析。”
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Tetsuo Adachi: "An arginine-213 to glycine mutation in human extracellular-superoxide dismutase reduces susceptibility to trypsin-like proteinases" Journal of Biochemistry. 120. 184-188 (1996)
Tetsuo Adachi:“人细胞外超氧化物歧化酶中精氨酸 213 向甘氨酸的突变降低了对胰蛋白酶样蛋白酶的敏感性”《生物化学杂志》。
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Tetsuo Adachi: "An arginine-213 to glycyine mutation in human extracellular-superoxide dismutase reduces susceptibility to trypsin-like proteinases" Journal of Biochemistry. 120. 184-188 (1996)
Tetsuo Adachi:“人细胞外超氧化物歧化酶中精氨酸 213 向甘氨酸的突变降低了对胰蛋白酶样蛋白酶的敏感性”《生物化学杂志》。
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北野 充: "腎とフリーラジカル" 加藤 克己,長瀬 光昌, 3 (1997)
北野充:《肾脏与自由基》加藤克己、长濑光政,3 (1997)
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共 11 条
Contribution of impairment of redox-regulation in development of Intraretinal microvascular abnormalities
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The medicine that functions to maintain the redox state might to the pathological conditions of insulin resistance
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财政年份:2003
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Dysfunction of protection enzymes of vascular endothelial cell surface results in the pathogenesis of cardiovascular disease
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项目类别:Grant-in-Aid for Scientific Research (C)
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资助金额:$2.11万
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依托单位:
Application of endothelial cell-binding superoxide dismutase (EC-SOD) on screening of the initiation-progress of renal diseases
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项目类别:Grant-in-Aid for Scientific Research (C)
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资助金额:$2.11万
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负责人:ADACHI Tetsuo
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依托单位:
海外基金