Leukotriene C4 secretion from normal murine mast cells by a probenecid-sensitive and multidrug resistance-associated protein-independent mechanism.

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Abstract
P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are members of the superfamily of ATP-binding cassette transporter proteins. Because the ATP-dependent export system has been implicated in the release of leukotriene C4 (LTC4), we examined the roles of P-gp and MRP in the release of LTC4 from normal murine mast cells (MC-9). We have previously shown that MC-9 cells express P-gp at the level of protein and mRNA. In the present study, MRP expression in MC-9 cells was examined at the protein level by anti-MRP Ab, using flow cytometry and at the level of mRNA by PCR and Northern blot analyses. MC-9 cells were stimulated with calcium ionophore A23187 for 15 min in the presence or the absence of various concentrations of cyclosporin A (CsA) and its nonimmunosuppressive analogue CsA-1, which are known to inhibit P-gp efflux function, or in the presence or the absence of probenecid, an organic ion transport inhibitor that appears to inhibit MRP-mediated transport function. Culture supernatants were collected, and LTC4 was measured by ELISA assay. CsA and CsA-1 had no effect on LTC4 secretion from MC-9 cells, suggesting that P-gp is not involved in LTC4 release from MC-9 cells. In contrast, probenecid, in a concentration-dependent manner, inhibited LTC4 secretion from MC-9 cells without inhibiting its synthesis. However, MC-9 lacked MRP at both the protein and mRNA levels. These data suggest that LTC4 is secreted by normal mast cells by a probenecid-sensitive mechanism that is independent of MRP.

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