Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal.
Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal.
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多药耐药蛋白 MRP1 可防止主要脂质过氧化产物 4-羟基壬烯醛的毒性。
DOI：
10.1042/bj3500555
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
M. Müller
中科院分区：
文献类型：
--
作者：
J. Renes;E. D. de Vries;G. Hooiveld;I. Krikken;P. Jansen;M. Müller
4-羟基壬烯醛（4 HNE）是氧化应激过程中形成的最常见的毒性脂质过氧化产物。它主要通过修饰细胞内蛋白质发挥其细胞毒性。在几种退行性疾病中检测到4 HNE修饰的蛋白表明4 HNE在这些疾病的发病中起作用。需要有效的保护机制来防止4 HNE的细胞内积累。用小细胞肺癌细胞系GLC（4）和多药耐药蛋白（MRP 1）过表达的对应物GLC（4）/Adr测试4 HNE的毒性。在MRP 1抑制剂MK 571或GSH消耗剂丁硫氨酸磺酰亚胺的存在下，两种细胞系变得更加敏感，并显示出存活率降低。使用（3）H-标记的4 HNE谷胱甘肽S-缀合物（[（3）H]GS-4 HNE）与来自GLC（4）衍生细胞系的膜囊泡（具有不同的MRP 1表达水平）进行转运实验。[（3）H]GS-4 HNE以ATP依赖的方式被摄取，转运速率依赖于MRP 1的量。MRP 1抑制剂MK 571可降低[（3）H]GS-4 HNE摄取。MRP 1特异性[（3）H]GS-4 HNE转运用来自过表达重组MRP 1的High Five昆虫细胞的膜囊泡证明。动力学实验显示表观K（m）为1.6+/-0.21 microM（平均值+/-S.D.）对MRP 1介导的[（3）H]GS-4 HNE转运的影响。总之，MRP 1具有对抗4 HNE毒性的作用，GS-4 HNE是一种新型MRP 1底物。MRP 1与GSH一起被假设在防御氧化应激中起作用。
4-Hydroxynonenal (4HNE) is the most prevalent toxic lipid peroxidation product formed during oxidative stress. It exerts its cytotoxicity mainly by the modification of intracellular proteins. The detection of 4HNE-modified proteins in several degenerative disorders suggests a role for 4HNE in the onset of these diseases. Efficient protection mechanisms are required to prevent the intracellular accumulation of 4HNE. The toxicity of 4HNE was tested with the small cell lung cancer cell lines GLC(4) and the multidrug-resistance-protein (MRP1)-overexpressing counterpart GLC(4)/Adr. In the presence of the MRP1 inhibitor MK571 or the GSH-depleting agent buthionine sulphoximine, both cell lines became more sensitive and showed decreased survival. Transport experiments were performed with the (3)H-labelled glutathione S-conjugate of 4HNE ([(3)H]GS-4HNE) with membrane vesicles from GLC(4)-derived cell lines with different expression levels of MRP1. [(3)H]GS-4HNE was taken up in an ATP-dependent manner and the transport rate was dependent on the amount of MRP1. The MRP1 inhibitor MK571 decreased [(3)H]GS-4HNE uptake. MRP1-specific [(3)H]GS-4HNE transport was demonstrated with membrane vesicles from High Five insect cells overexpressing recombinant MRP1. Kinetic experiments showed an apparent K(m) of 1.6+/-0.21 microM (mean+/-S.D.) for MRP1-mediated [(3)H]GS-4HNE transport. In conclusion, MRP1 has a role in the protection against 4HNE toxicity and GS-4HNE is a novel MRP1 substrate. MRP1, together with GSH, is hypothesized to have a role in the defence against oxidative stress.
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影响因子：
6.5
作者：
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通讯作者：
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影响因子：
7.4
作者：
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通讯作者：
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
11.2
作者：
Chung,FL;Nath,RG;Ocando,J;Nishikawa,A;Zhang,L
通讯作者：
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