Transport of leukotriene C4 and structurally related conjugates.
Transport proteins control the release of the endogenous glutathione conjugate leukotriene C4 (LTC4) from leukotriene-synthesizing cells as well as its hepatobiliary and renal elimination. The photolabile conjugated triene structure of LTC4 has enabled direct photoaffinity labeling of the multidrug resistance protein 1 (MRP1, symbol ABC C1) in membranes from mastocytoma cells, leading to the identification of the function of this protein as an ATP-dependent export pump for LTC4 and structurally related conjugates. MRP1 is assigned to the C branch of the superfamily of ATP-binding cassette (ABC) transporters and was originally identified by virtue of its association with drug resistance in tumor cells. Besides LTC4, which is a high-affinity substrate, a variety of conjugates of hydrophobic endogenous or xenobiotic substances with glutathione, glucuronate, or sulfate are transported by MRP1. In addition, hydrophobic compounds may undergo cotransport with glutathione. Effective inhibitors of MRP1-mediated transport include structural analogs of LTC4 and of other cysteinyl leukotrienes. The ATP-dependent transport system which transports cysteinyl leukotrienes across the hepatocyte canalicular membrane into bile was cloned and characterized as the second isoform or paralog of the mammalian MRP family, MRP2 (ABC C2). MRP2 is localized to the apical membrane of polarized cells. The overall substrate specificities of MRP1 and MRP2 are similar, despite an amino acid identity of only 48%. The transport proteins mediating the uptake of LTC4 into hepatocytes across the basolateral membrane are members of the organic anion transporter (OATP) branch of the solute carrier (SLC) superfamily and are thus distinct from the ATP-dependent export pumps of the MRP family.
Jedlitschky
Gabriele
G
Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.
Keppler
Dietrich
D
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D006801:Humans; D017997:Leukotriene C4 / Q000096:biosynthesis / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins