Characterization of Vincristine Transport by the Mr 190,000 Multidrug Resistance Protein (MRP): Evidence for Cotransport with Reduced Glutathione

摘要: Abstract The Mr 190,000 multidrug resistance protein (MRP) confers to a broad spectrum of natural product drugs. However, it has not been possible demonstrate that MRP can actively transport unmodified forms these compounds, although the shown structurally diverse glutathione (GSH)- and glucuronide-conjugated molecules. Previously, we showed ATP-dependent uptake vincristine by MRP-enriched, inside-out membrane vesicles could be stimulated physiological concentrations GSH (Loe et al., J. Biol. Chem., 271: 9675–9682, 1996). We have now established ATP/GSH dependent is both proportional level in inhibited monoclonal antibodies previously inhibit substrates, such as leukotriene C4. also show short-chain alkyl derivatives stimulate drug uptake, which suggests does necessarily involve change redox state or glutathionylation protein. Furthermore, accompanied ATP- drug-dependent accumulation GSH, lesser extent vinblastine but daunorubicin doxorubicin. Although alone are very poor inhibitors MRP-mediated C4, together they act relatively potent competitive inhibitors. Overall, our data cotransport compounds probably interact, either with C4 binding site(s) on mutually exclusive site.