ATP-Dependent Transport of Aflatoxin B1and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene
| Autor: | Douglas W. Loe, Thomas E. Massey, Roger G. Deeley, Richard K. Stewart, Susan P.C. Cole |
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| Rok vydání: | 1997 |
| Předmět: |
Aflatoxin
Aflatoxin B1 Lung Neoplasms Biological Transport Active ATP-binding cassette transporter Tritium Substrate Specificity chemistry.chemical_compound Adenosine Triphosphate stomatognathic system Tumor Cells Cultured Humans Drug Interactions ATP Binding Cassette Transporter Subfamily B Member 1 Carcinoma Small Cell Chromatography High Pressure Liquid Carcinogen Pharmacology Chemistry Vesicle Stereoisomerism Glutathione Membrane transport Drug Resistance Multiple Kinetics Biochemistry Carcinogens Molecular Medicine ATP-Binding Cassette Transporters Multidrug Resistance-Associated Proteins Multiple Myeloma Adenosine triphosphate |
| Zdroj: | Molecular Pharmacology. 51:1034-1041 |
| ISSN: | 1521-0111 0026-895X |
| Popis: | 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 mM GSH, 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. |
| Databáze: | OpenAIRE |
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