Role of multidrug-resistance protein 2 in glutathione S-transferase P1-1-mediated resistance to 4-nitroquinoline 1-oxide toxicities in HepG2 cells

Mol Carcinog. 2000 Nov;29(3):170-8. doi: 10.1002/1098-2744(200011)29:3<170::aid-mc6>3.0.co;2-w.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 4-Nitroquinoline-1-oxide / pharmacokinetics
  • 4-Nitroquinoline-1-oxide / toxicity*
  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Carcinogens / pharmacokinetics
  • Carcinogens / toxicity*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Division / physiology
  • Cyclosporine / pharmacology
  • Drug Resistance, Neoplasm
  • Glutathione S-Transferase pi
  • Glutathione Transferase / biosynthesis
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism*
  • Humans
  • Inactivation, Metabolic
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / metabolism*
  • Membrane Transport Proteins*
  • Multidrug Resistance-Associated Proteins*
  • Protein Isoforms
  • Sulfinpyrazone / pharmacology
  • Transfection
  • Tumor Cells, Cultured / drug effects

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Carcinogens
  • Isoenzymes
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Protein Isoforms
  • multidrug resistance-associated protein 2
  • 4-Nitroquinoline-1-oxide
  • Cyclosporine
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • Glutathione Transferase
  • Sulfinpyrazone
  • multidrug resistance-associated protein 1