Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein
Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein
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DOI：
10.1038/nm1197-1275
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发表时间：
1997-11-01
期刊：
影响因子：
82.9
通讯作者：
Borst, P
中科院分区：
文献类型：
--
作者：
Wijnholds, J;Evers, R;Borst, P
The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (CS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes(1-5). 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 inflam matory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C-4 (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(6) GS-X pump's is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.
