Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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4-Nitroquinoline-1-oxide / pharmacokinetics
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4-Nitroquinoline-1-oxide / toxicity*
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / metabolism*
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Carcinogens / pharmacokinetics
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Carcinogens / toxicity*
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Carcinoma, Hepatocellular / enzymology
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Carcinoma, Hepatocellular / metabolism*
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Cell Division / physiology
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Cyclosporine / pharmacology
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Drug Resistance, Neoplasm
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Glutathione S-Transferase pi
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Glutathione Transferase / biosynthesis
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Glutathione Transferase / genetics
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Glutathione Transferase / metabolism*
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Humans
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Inactivation, Metabolic
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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Isoenzymes / metabolism*
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Liver Neoplasms / enzymology
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Liver Neoplasms / metabolism*
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Membrane Transport Proteins*
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins*
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Protein Isoforms
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Sulfinpyrazone / pharmacology
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Transfection
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Tumor Cells, Cultured / drug effects
Substances
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ABCC2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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Carcinogens
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Isoenzymes
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Membrane Transport Proteins
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Multidrug Resistance-Associated Protein 2
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Multidrug Resistance-Associated Proteins
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Protein Isoforms
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4-Nitroquinoline-1-oxide
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Cyclosporine
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GSTP1 protein, human
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Glutathione S-Transferase pi
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Glutathione Transferase
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Sulfinpyrazone
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multidrug resistance-associated protein 1