Lorico Aurelio, Bertola Antonella, Baum Christopher, Fodstad Oystein, Rappa Germana
Department of Tumor Biology, Norwegian Radium Hospital, Montebello, 0310, Norway.
Biochem Biophys Res Commun. 2002 Mar 1;291(3):617-22. doi: 10.1006/bbrc.2002.6489.
The Multidrug Resistance Protein 1 (MRP1) is a membrane pump that mediates the efflux of a wide variety of xenobiotics, including arsenical and antimonial compounds, as demonstrated by the study of MRP1-transfected cell lines. We have previously shown that mrp1(-/-) cells are hypersensitive to sodium arsenite, sodium arsenate, and antimony potassium tartrate. We now report that the retroviral vector-mediated overexpression of MRP1 and of the two subunits of gamma-GCS (heavy and light) resulted in higher intracellular glutathione levels and in a greater level of resistance to sodium arsenite and antimony potassium tartrate, compared to the overexpression of MRP1 and gamma-GCS heavy alone. These observations further demonstrate that glutathione is an important component of MRP1-mediated cellular resistance to arsenite and antimony. However, the constitutive expression of MRP1 did not protect mice from the lethality of sodium arsenite and antimony potassium tartrate nor reduced the tissue accumulation of arsenic in mice injected i.p. with sodium arsenite. It is conceivable that, in vivo, other pump(s) effectively vicariate for MRP1-mediated transport of heavy metal oxyanions.
多药耐药蛋白1（MRP1）是一种膜泵，可介导多种外源性物质的外排，包括砷化合物和锑化合物，这已在对MRP1转染细胞系的研究中得到证实。我们之前已经表明，mrp1（-/-）细胞对亚砷酸钠、砷酸钠和酒石酸锑钾高度敏感。我们现在报告，与单独过表达MRP1和γ-GCS重链相比，逆转录病毒载体介导的MRP1以及γ-GCS的两个亚基（重链和轻链）的过表达导致细胞内谷胱甘肽水平升高，并且对亚砷酸钠和酒石酸锑钾的抗性增强。这些观察结果进一步证明，谷胱甘肽是MRP1介导的细胞对亚砷酸盐和锑抗性的重要组成部分。然而，MRP1的组成型表达并不能保护小鼠免受亚砷酸钠和酒石酸锑钾致死作用的影响，也不能减少腹腔注射亚砷酸钠的小鼠体内砷的组织蓄积。可以想象，在体内，其他泵可有效地替代MRP1介导的重金属含氧阴离子的转运。
