Evidence for a multidrug resistance-associated protein 1 (MRP1)-related transport system in cultured rat liver biliary epithelial cells

Cellular accumulation and efflux of the anionic fluorescent dye carboxy-2', 7'-dichlorofluorescein (CF) were studied in rat liver SDVI cells thought to derive from primitive bile ductules, in order to characterize carrier-rela ted membrane transport of organic anions in epithelial cells. Probenecid, a common blocker of anion transport, was found to strongly enhance CF levels in SDVI cells in a dose-dependent manner through inhibition of dye efflux. Such an outwardly-directed transport was demonstrated to be temperature-de pendent and down-regulated by various metabolic inhibitors, therefore outli ning its requirement for energy; it was shown to be Na+- and membrane poten tial-independent and inhibited by anionic drugs such as indomethacin, indop rofen and rifamycin B. These functional features are closed to those descri bed for multidrug resistance-associated protein 1 (MRP1) that was furthermo re demonstrated, in contrast to P-glycoprotein, to be expressed in SDVI cel ls and to lower CF accumulation in MRP1-overexpressing drug-resistant tumor cells. These data therefore suggest that active membrane transport of orga nic anions such as CF occurs in epithelial cells like cultured liver biliar y SDVI cells through a MRP1-related efflux system.