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. ? ? ?
| Sivils, Jeffrey C; Ancrum, Tiffany M; Bain, Lisa J (2013) LOSS of Mrp1 alters detoxification enzyme expression in a tissue- and hormonal-status-specific manner. J Appl Toxicol 33:766-73 |
| Sivils, Jeffrey C; Gonzalez, Iven; Bain, Lisa J (2010) Mice lacking Mrp1 have reduced testicular steroid hormone levels and alterations in steroid biosynthetic enzymes. Gen Comp Endocrinol 167:51-9 |
