Role of multidrug-resistance protein 2 in glutathione S-transferase P1-1-mediated resistance to 4-nitroquinoline 1-oxide toxicities in HepG2 cells.
Previous studies in our laboratory have shown that the phase III efflux transporter multidrug-resistance protein (MRP)1 can act synergistically with the phase II conjugating glutathione S-transferases (GST) to confer resistance to the toxicities of some electrophilic drugs and carcinogens. To determine whether the distinct efflux transporter MRP2 could also potentiate GST-mediated protection from electrophilic toxins, we examined the effect of regulatable GSTP1-1 expression in MRP2-rich HepG2 cells on 4-nitroquinoline 1-oxide (4NQO)-induced cytotoxicity and genotoxicity (nucleic-acid adduct formation). Expression of GSTP1-1 was associated with a fourfold to tenfold protection from 4NQO-induced cytotoxicity. Inhibition of MRP2-mediated efflux activity by sulfinpyrazone or cyclosporin A completely reversed GSTP1-1-associated resistance-a result indicating that GSTP1-1-mediated cytoprotection is absolutely dependent on MRP2 efflux activity. Moreover, MRP2 efflux activity also augmented GSTP1-1-mediated protection from 4NQO-induced nucleic-acid adduct formation. We conclude that MRP2-mediated efflux of the glutathione conjugate of 4NQO and/or another toxic derivative of 4NQO is required to support GSTP1-1-associated protection from 4NQO toxicities in HepG2 cells.
Morrow
C S
CS
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Smitherman
P K
PK
Townsend
A J
AJ
D015112:4-Nitroquinoline-1-oxide / Q000493:pharmacokinetics / Q000633:toxicity*; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism*; D002455:Cell Division / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008658:Inactivation, Metabolic; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism*; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020033:Protein Isoforms; D013442:Sulfinpyrazone / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015112:4-Nitroquinoline-1-oxide; D018435:ATP Binding Cassette Transporter, Subfamily B; D002273:Carcinogens; D016572:Cyclosporine; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020033:Protein Isoforms; D013442:Sulfinpyrazone; C000715087:ABCC2 protein, human; C496556:GSTP1 protein, human; C421109:multidrug resistance-associated protein 1