%0 Journal Article %A Douglas W. Loe %A Richard K. Stewart %A Thomas E. Massey %A Roger G. Deeley %A Susan P. C. Cole %T ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene %D 1997 %R 10.1124/mol.51.6.1034 %J Molecular Pharmacology %P 1034-1041 %V 51 %N 6 %X 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. %U https://molpharm.aspetjournals.org/content/molpharm/51/6/1034.full.pdf