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Vol. 54, Issue 2, 298-304, August 1998
Biochemistry Department and Wake Forest University Comprehensive
Cancer Center, Wake Forest University School of Medicine,
Winston-Salem, North Carolina 27157 (W.R.F., C.S.M., A.J.T.) and
Institute of Environmental Medicine, Division of Biochemical
Toxicology, Karolinska Institutet, Stockholm, Sweden (K.S., B.J.)
The (+)-anti enantiomer of
benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE) is
a potent mutagenic and carcinogenic metabolite of
benzo[a]pyrene (BP), and a major fraction is
conjugated with glutathione in vivo. The chemopreventive
role of glutathione S-transferases (GSTs) in protecting
against covalent modification of DNA and other cellular macromolecules
by BPDE was modeled in human T47D and MCF-7 cell lines previously
stably transfected with human GST
1 (hGSTP1). Cells were exposed to
[3H]BPDE (30-600 nM). Dose-response
experiments indicated that the high level of expression of hGSTP1-1 in
the T47D cell line (4411 ± 183 milliunits/mg of cytosolic
protein, using 1-Cl-2,4-dinitrobenzene as substrate), resulted in
70-90% reduction in the covalent 3H-adduct formation in
DNA or RNA isolated from the GSTP1-transfected T47D cell line. The
lower level of hGSTP1-1 expression in the transfected MCF-7 cell line
(91 milliunits/mg) provided only marginal protection against
[3H]BPDE adduct formation and did not affect sensitivity
to BPDE-induced cytotoxicity. Protection against BPDE-induced
cytotoxicity was observed only in the T47D cell line, which had an
IC50 value 5.8-fold greater than that of the
T47Dneo control cell line. Measurement of
glutathione conjugates of BPDE indicated that the total conjugation was
5-fold higher in the GST-transfected T47D line, most of which was
exported into the culture medium over the 20-min exposure period. These
results indicate that hGSTP1-1 protects effectively against DNA and
RNA modification by BPDE, but moderate to high level expression may be
required for strong protection against BPDE-induced genotoxicity and
cytotoxicity.
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