Substrate recognition and transport by multidrug resistance protein 1 (ABCC1)

Abstract 

Multidrug resistance protein (MRP) 1 belongs to the ‘C’ branch of the ABC transporter superfamily. MRP1 is a high-affinity transporter of the cysteinyl leukotriene C₄ and is responsible for the systemic release of this cytokine in response to an inflammatory stimulus. However, the substrate specificity of MRP1 is extremely broad and includes many organic anion conjugates of structurally unrelated endo- and xenobiotics. In addition, MRP1 transports unmodified hydrophobic compounds, such as natural product type chemotherapeutic agents and mutagens, such as aflatoxin B₁. Transport of several of these compounds has been shown to be dependent on the presence of reduced glutathione (GSH). More recently, GSH has also been shown to stimulate the transport of some conjugated compounds, including sulfates and glucuronides. Here, we summarize current knowledge of the substrate specificity and modes of transport of MRP1 and discuss how the protein may recognize its structurally diverse substrates.

Abbreviations: BSO, buthionine sulfoximine, LTC₄, leukotriene C₄, MRP1, multidrug resistance protein 1, P-gp, P-glycoprotein, CFTR, cystic fibrosis transmembrane conductance regulator, E₂17βG, estradiol-17β-d-glucuronide, GSH, glutathione, NBD, nucleotide-binding domain, MSD, membrane spanning domain, SUR, sulfonylurea receptor, MALDI TOF, matrix-assisted laser desorption/ionization time of flight, NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, TM, transmembrane

Keywords: Multidrug resistance protein 1, Leukotriene C₄, Glutathione, Atomic homology model, Site-directed mutagenesis, Organic anion transport, ABC transporter, Multidrug resistance