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Molecular Pharmacology

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Research ArticleArticle

ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene

Douglas W. Loe, Richard K. Stewart, Thomas E. Massey, Roger G. Deeley and Susan P. C. Cole
Molecular Pharmacology June 1997, 51 (6) 1034-1041; DOI: https://doi.org/10.1124/mol.51.6.1034
Douglas W. Loe
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Richard K. Stewart
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Thomas E. Massey
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Roger G. Deeley
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Susan P. C. Cole
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Abstract

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.

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Molecular Pharmacology: 51 (6)
Molecular Pharmacology
Vol. 51, Issue 6
1 Jun 1997
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Research ArticleArticle

ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene

Douglas W. Loe, Richard K. Stewart, Thomas E. Massey, Roger G. Deeley and Susan P. C. Cole
Molecular Pharmacology June 1, 1997, 51 (6) 1034-1041; DOI: https://doi.org/10.1124/mol.51.6.1034

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Research ArticleArticle

ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene

Douglas W. Loe, Richard K. Stewart, Thomas E. Massey, Roger G. Deeley and Susan P. C. Cole
Molecular Pharmacology June 1, 1997, 51 (6) 1034-1041; DOI: https://doi.org/10.1124/mol.51.6.1034
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