TY - JOUR T1 - ATP-Dependent Transport of Aflatoxin B<sub>1</sub> and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (<em>MRP</em>) Gene JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1034 LP - 1041 DO - 10.1124/mol.51.6.1034 VL - 51 IS - 6 AU - Douglas W. Loe AU - Richard K. Stewart AU - Thomas E. Massey AU - Roger G. Deeley AU - Susan P. C. Cole Y1 - 1997/06/01 UR - http://molpharm.aspetjournals.org/content/51/6/1034.abstract N2 - Glutathione-S-transferase-catalyzed conjugation of glutathione (GSH) to aflatoxin B1-8,9-epoxide plays an important role in preventing binding of this ultimate carcinogen to target macromolecules. Once formed, the aflatoxin B1-epoxide-GSH conjugates are actively extruded from the cell by an unidentified ATP-dependent export pump or pumps. Two possible candidates for this GSH conjugate pump are the 190-kDa multidrug resistance protein (MRP) and the 170-kDa P-glycoprotein. Both proteins belong to the ATP-binding cassette superfamily of transmembrane transport proteins and confer resistance to a similar spectrum of natural-product drugs. Using membrane vesicles from MRP-transfected cells, we found that MRP transports GSH conjugates of both the endo-isomers and exo-isomers of aflatoxin B1-8,9-epoxide in an ATP-dependent, osmotically sensitive manner (V max = 180 pmol/mg/min,K m = 189 nm). Membrane vesicles from P-glycoprotein-overexpressing cells showed very low levels of transport. MRP-mediated transport was inhibited by an MRP-specific monoclonal antibody and by a variety of GSH derivatives and cholestatic steroid glucuronides. ATP-dependent transport of unmodified aflatoxin B1 by MRP-enriched membrane vesicles was low but markedly enhanced in the presence of 5 mmGSH, even though GSH conjugates of aflatoxin B1 were not formed by the vesicles. These data demonstrate that MRP is capable of energy-dependent transport of aflatoxin B1 and its GSH conjugates and suggest a potential protective role for MRP in mammalian chemical carcinogenesis. ER -