Does the Lack of MRP1 Alter Expression of Other Genes?

描述(申请人提供)：多药耐药相关蛋白1(MRP1/ABCC1)是三磷酸腺苷结合盒(ABC)蛋白家族的成员。作为这个转运蛋白家族的成员，主要将葡萄糖醛酸、谷胱甘肽和硫酸盐结合的化合物转运出细胞，已经产生了缺乏MRP1蛋白的小鼠(称为FVB/MRPL-/-小鼠)。虽然这些动物是活的和有生育能力的，但MRP1显然在保护小鼠免受各种化合物的毒性方面发挥了作用，包括像依托泊苷这样的抗癌药物。在初步研究中，我们已经证明MRP1也可以保护睾丸小管免受甲氧氯胺的毒性。在研究过程中，我们意识到与FVB/MRPL-/-小鼠相比，对照野生型小鼠中几种细胞色素P450蛋白的活性显著降低。因此，我们想进一步研究缺乏多药耐药相关蛋白1(MRPI/ABCC1)的小鼠与野生型小鼠在基因表达上的差异。需要检验的假设是，这种转运蛋白的缺失虽然不是致命的，但会导致多种基因的上调和下调，以补偿其缺失，可能是以组织特有的方式。利用这些信息，我们可以更好地理解转运蛋白和其他调节它们的基因之间的协调调节，或者是处于解毒和消除途径中的基因。这些信息最终将对利用这些小鼠来确定药物处置和抗癌药物的效力或特异性具有无价的价值。

DESCRIPTION (provided by applicant): The multidrug resistance-associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) protein family. Member of this family of transporters actively transport predominantly glucuronide, glutathione, and sulfate conjugated compounds out of cells, Mice lacking the MRP1 protein (termed FVB/mrpl-/- mice) have been produced. While the animals are viable and fertile, MRP1 clearly plays a role in protecting the mice from the toxicity of a variety of compounds, including anticancer drugs such as etoposide. In preliminary studies, we have shown that MRP1 also protects the testicular tubules from methoxychlor toxicity. During the course of that study, we realized that activity of several cytochrome P450 proteins was significantly lowered in control wild type mice compared to control FVB/mrpl-/- mice. Therefore, we would like to further examine the differences in gene expression in mice lacking the multidrug resistance-associated protein 1 (MRPI/ABCC1) compared to wild-type mice. The hypothesis to be tested is that the loss of this transporter, while not lethal, results in the up- and down-regulation of a variety of genes to compensate for its loss, presumably in a tissue-specific manner. Using this information, we can better understand coordinate regulation between transporters and other genes that regulate them, or genes that are in detoxification and elimination pathways. This information will ultimately be invaluable for using these mice to determine drug disposition and the potency or specificity of anticancer drugs.