Glutathione S-conjugate transport in hepatocytes entering the cell cycle is preserved by a switch in expression from the apical MRP2 to the basolateral MRP1 transporting protein

The multidrug resistance protein MRP1 and its isoform MRP2 are involved in ATP-dependent glutathione S-conjugate transport and have similar substrate specificities. MRP2 mediates hepatic organic anion transport into bile. The physiological function of MRP1 in hepatocytes is unknown. Previous results show that MRP1 expression is low in quiescent hepatocytes but increased af ter SV40 large T antigen immortalization, suggesting a relationship with ce ll proliferation. Therefore, we determined mrp1 and mrp2 expression in rat hepatocytes in relation to the cell cycle. By varying cell density we obtai ned cultures that are mainly in G(1) (high density) or have progressed into the S-phase or beyond (low density). In both cultures mrp1 mRNA and protei n levels are increased, concomitantly with the disappearance of mrp2, This switch from mrp2 to mrp1 occurs in the G(1) phase of the cell cycle and is associated with a decreased cell polarity, Mrp1 is located on lateral membr anes or on intracellular vesicles, depending on whether cell-cell contact i s established. In both locations mrp1 contributes to cellular glutathione S -conjugate efflux and protects against oxidative stress-inducing quinones. We conclude that a switch in expression from the apically located mrp2 to t he basolaterally located mrp1 preserves glutathione S-conjugate transport i n hepatocytes entering the cell cycle and protects against certain cytotoxi c agents.