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The Journal of Lipid Research, Vol. 40, 439-446, March 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Characterization of a leukotriene C₄ export mechanism in human platelets: possible involvement of multidrug resistance-associated protein 1

Correspondence to: Mikael Sjölinder

Platelets express leukotriene (LT) C₄ synthase and can thus participate in the formation of bioactive LTC₄. To further elucidate the relevance of this capability, we have now determined the capacity of human platelets to export LTC₄. Endogenously formed LTC₄ was efficiently released from human platelets after incubation with LTA₄ at 37°C, whereas only 15% of produced LTC₄ was exported when the cells were incubated at 0°C. The activation energy of the process was calculated to 49.9 ± 7.7 kJ/mol, indicating carrier-mediated LTC₄ export. This was also supported by the finding that the transport was saturable, reaching a maximal export rate of 470 ± 147 pmol LTC₄/min x 10⁹ platelets. Furthermore, markedly suppressed LTC₄ transport was induced by a combination of the metabolic inhibitors antimycin A and 2-deoxyglucose, suggesting energy-dependent export.

The presence in platelets of multidrug resistance-associated protein 1 (MRP1), a protein described to be an energy-dependent LTC₄ transporter in various cell types, was demonstrated at the mRNA and protein level. Additional support for a role of MRP1 in platelet LTC₄ export was obtained by the findings that the process was inhibited by probenecid and the 5-lipoxygenase-activating protein (FLAP) inhibitor, MK-886. The present findings further support the physiological relevance of platelet LTC₄ production.—Sjölinder, M., S. Tornhamre, H-E. Claesson, J. Hydman, and J. Å. Lindgren. Characterization of a leukotrine C₄ export mechanism in human platelets: possible involvement of multidrug resistance-associated protein. J. Lipid Res. 1999. 40: 439– 446.

Supplementary key words: active transport, LTA₄ metabolism, immunoblot, RT-PCR

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