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

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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. Mol. Carcinog. 29:170–178, 2000.