Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein
- PMID: 9359705
- DOI: 10.1038/nm1197-1275
Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein
Abstract
The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp-/-, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C4 (LTC4) from leukotriene-synthesizing cells. Moreover, the mrp-/- mice are hypersensitive to the anticancer drug etoposide. The phenotype of mrp-/- mice is consistent with a role for MRP as the main LTC4-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous GS-X pump is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.
Similar articles
-
Doxorubicin- and daunorubicin-glutathione conjugates, but not unconjugated drugs, competitively inhibit leukotriene C4 transport mediated by MRP/GS-X pump.Biochem Biophys Res Commun. 1998 Jun 29;247(3):859-63. doi: 10.1006/bbrc.1998.8887. Biochem Biophys Res Commun. 1998. PMID: 9647783
-
The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion.Adv Enzyme Regul. 1996;36:17-29. doi: 10.1016/0065-2571(95)00011-9. Adv Enzyme Regul. 1996. PMID: 8869738
-
Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells.Mol Pharmacol. 1997 Sep;52(3):344-53. doi: 10.1124/mol.52.3.344. Mol Pharmacol. 1997. PMID: 9281595
-
Do cMOAT (MRP2), other MRP homologues, and LRP play a role in MDR?Semin Cancer Biol. 1997 Jun;8(3):205-13. doi: 10.1006/scbi.1997.0071. Semin Cancer Biol. 1997. PMID: 9441949 Review.
-
[Multidrug resistance protein (MRP)].Nihon Rinsho. 1997 May;55(5):1077-82. Nihon Rinsho. 1997. PMID: 9155156 Review. Japanese.
Cited by
-
Tyrosine kinase inhibitors as modulators of ABC transporter-mediated drug resistance.Drug Resist Updat. 2012 Feb-Apr;15(1-2):70-80. doi: 10.1016/j.drup.2012.01.005. Epub 2012 Feb 9. Drug Resist Updat. 2012. PMID: 22325423 Free PMC article. Review.
-
Angiotensin II triggers release of leukotriene C4 in vascular smooth muscle cells via the multidrug resistance-related protein 1.Mol Cell Biochem. 2010 Jan;333(1-2):261-7. doi: 10.1007/s11010-009-0227-x. Epub 2009 Aug 15. Mol Cell Biochem. 2010. PMID: 19685171
-
Multidrug resistance protein 1 (MRP1) in rabbit conjunctival epithelial cells: its effect on drug efflux and its regulation by adenoviral infection.Pharm Res. 2007 Aug;24(8):1490-500. doi: 10.1007/s11095-007-9267-7. Epub 2007 Apr 3. Pharm Res. 2007. PMID: 17404811
-
MRP1 gene expression level regulates the death and differentiation response of neuroblastoma cells.Br J Cancer. 2001 Nov 16;85(10):1564-71. doi: 10.1054/bjoc.2001.2144. Br J Cancer. 2001. PMID: 11720446 Free PMC article.
-
Multidrug resistance-associated protein 1 as a major mediator of basal and apoptotic glutathione release.Biochim Biophys Acta. 2008 Oct;1778(10):2413-20. doi: 10.1016/j.bbamem.2008.06.011. Epub 2008 Jun 21. Biochim Biophys Acta. 2008. PMID: 18621020 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Miscellaneous