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首页> 外文期刊>The biochemical journal >Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal
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Multidrug resistance protein MRP1 protects against the toxicity of the major lipid peroxidation product 4-hydroxynonenal

机译：多药抗性蛋白MRP1可保护主要脂质过氧化产物4-羟基诺的毒性

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摘要

p4-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 GLCsub4/sub and the multidrug-resistance-protein (MRP1)-overexpressing counterpart GLCsub4/sub/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 sup3/supH-labelled glutathione S-conjugate of 4HNE ([sup3/supH]GS-4HNE) with membrane vesicles from GLCsub4/sub-derived cell lines with different expression levels of MRP1. [sup3/supH]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 [sup3/supH]GS-4HNE uptake. MRP1-specific [sup3/supH]GS-4HNE transport was demonstrated with membrane vesicles from High Five insect cells overexpressing recombinant MRP1. Kinetic experiments showed an apparent iK/isubm/sub of 1.6±0.21iμ/iM (mean±S.D.) for MRP1-mediated [sup3/supH]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./p
机译：

4-羟基诺（4HNE）是在氧化应激期间形成的最普遍的有毒脂质过氧化产物。它主要通过细胞内蛋白的改性来施加其细胞毒性。在几种退行性疾病中检测4HNE改性的蛋白质表明在这些疾病的发作中的4hne作用。需要有效的保护机制来防止4HNE的细胞内积聚。用小细胞肺癌细胞系Glc 4 和多药抗性 - 蛋白（MRP1）-overxcressing对应Glc 4 / Adr进行毒性。在MRP1抑制剂MK571或GSH耗尽剂BATHIONINININININININININININININ磺酰胺存在下，两种细胞系变得更加敏感并且显示出降低的存活率。用来自GLC 4的膜囊泡的膜囊泡的 3 H标记的谷胱甘肽S缀合物进行运输实验。具有不同表达水平的MRP1的亚>的细胞系。以ATP依赖性方式溶出[Sup> 3 H] GS-4HNE，传输速率取决于MRP1的量。 MRP1抑制剂MK571降低[ 3 h] gs-4hne吸收。 MRP1特异性[ 3 H] GS-4HNE转运，用来自过表达的重组MRP1的高五种昆虫细胞的膜囊泡进行了说明。动力学实验表明，MRP1介导的1.6±0.21℃（平均值±SD）[ 3 <] / sup> h] gs-4hne运输。总之，MRP1在防止毒性和GS-4HNE的保护中具有新的MRP1底物。 MRP1与GSH一起被假设在防御氧化应激方面具有作用。

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