Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity

• Published in: Carcinogenesis (New York) Vol. 19; no. 1; pp. 109 - 115
• Main Authors: MORROW, C. S, DIAH, S, SMITHERMAN, P. K, SCHNEIDER, E, TOWNSEND, A. J
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 1998
• Subjects: 4-Nitroquinoline-1-oxide - pharmacokinetics; 4-Nitroquinoline-1-oxide - toxicity; ATP-Binding Cassette Transporters - biosynthesis; Biological and medical sciences; Breast Neoplasms; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - pharmacokinetics; Carcinogens - toxicity; Cell Survival - drug effects; Chemical agents; Drug Resistance, Multiple; Female; Glutathione - metabolism; Glutathione Transferase - biosynthesis; Humans; Isoenzymes - biosynthesis; Kinetics; Medical sciences; Multidrug Resistance-Associated Proteins; Recombinant Proteins - biosynthesis; Transfection; Tumor Cells, Cultured; Tumors; Enzyme; Toxicity; Transferases; Malignant tumor; Carcinogenesis; In vitro; Prevention; Mammary gland diseases; Carcinogen; Glutathione transferase; DNA; Multiple resistance; Established cell line; Mammary gland; Mechanism of action; Molecular adduct; Tumor cell
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/19.1.109

Model cell lines developed from MCF7 breast carcinoma cells were used to examine the roles of glutathione S-transferase P1-1 (GSTP1-1) and multidrug resistance protein (MRP) in the protection of cells from 4-nitroquinoline 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 protection from 4NQO-mediated cytotoxicity. Increased expression of MRP alone conferred modest protection while co-expression of GSTP1-1 with MRP produced high-level protection from both 4NQO-derived adduct formation and 4NQO cytotoxicity. This synergistic resistance to 4NQO toxicities (both nucleic acid adduct formation and cytotoxicity) is associated with a GSTP1-1-dependent increase in 4NQO-glutathione (QO-SG) conjugate formation and a MRP-dependent increase in QO-SG efflux. These data indicate that MRP is an important export transporter for the glutathione conjugate of the carcinogen, 4NQO. Moreover, this MRP-dependent efflux activity is necessary to achieve the full protection from 4NQO toxicity-protection that is potentiated by GSTP1-1-mediated QO-SG formation.