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From the Cancer Research Laboratories (D.W.L., R.G.D., S.P.C.C.),
Department of Pharmacology and Toxicology (R.K.S., T.E.M., S.P.C.C.),
and
Department of Medicine (T.E.M.), Queen's University, Kingston,
Ontario K7L 3N6, Canada
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 (Vmax = 180 pmol/mg/min,
Km = 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.
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