Carcinogenesis, Vol 19, 109-115, Copyright © 1998 by Oxford University Press
CS Morrow, S Diah, PK Smitherman, E Schneider and AJ Townsend
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.
ARTICLES
Multidrug resistance protein and glutathione S-transferase P1-1 act in synergy to confer protection from 4-nitroquinoline 1-oxide toxicity
Department of Biochemistry, Bowman Gray School of Medicine, Winston- Salem, NC 27157-1016, USA. cmorrow@bgsm.edu
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