MULTIDRUG-RESISTANCE PROTEIN AND GLUTATHIONE-S-TRANSFERASE P1-1 ACT IN SYNERGY TO CONFER PROTECTION FROM 4-NITROQUINOLINE 1-OXIDE TOXICITY

Model cell lines developed from MCM breast carcinoma cells were used t o examine the roles of glutathione S-transferase p1-1 (GSTP1-1) and mu ltidrug resistance protein (MRP) in the protection of cells from 4-nit roquinoline 1-oxide (4NQO) toxicities, Increased expression of GSTP1-1 alone in MCF7 cells results in limited protection from the formation of 4NQO-derived covalent adducts of nucleic acids but affords no prote ction from 4NQO-mediated cytotoxicity. Increased expression of MRP alo ne conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formatio n and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicitie s (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO-SG) conjugat e formation and a MRP-dependent increase in QO-SG efflux, These data i ndicate that MRP is an important export transporter for the glutathion e conjugate of the carcinogen, 4NQO, Moreover, this MRP-dependent effl ux activity is necessary to achieve the full protection from 4NQO toxi city-protection that is potentiated by GSTP1-1-mediated QO-SG formatio n.