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Carcinogenesis |
Department of Environmental Health Sciences [C. P. N., L. R. K., J. D. G., T. W. K.], Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205, and Departments of Oncology [J. S., W. B. I., W. G. N., J. D. G., T. W. K.], Urology [J. S., W. B. I., W. G. N.], Pathology [A. M. D.], Pharmacology and Molecular Sciences [W. G. N., T. W. K.], and Medicine [W. G. N.], Johns Hopkins University School of Medicine, Baltimore, Maryland 21287
The prostate has been identified as a target for
2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
(PhIP)-induced carcinogenesis. Humans are exposed to PhIP through
ingestion of well-done cooked meats, and there is evidence from
epidemiological studies that implicates red meat consumption in
prostate carcinogenesis. The 
and 
class isoforms of glutathione
S-transferases (GSTs) have been shown to inhibit
adduction of activated PhIP metabolites to DNA in cell-free systems. In
humans, silencing of GST (GSTP1) through CpG island
hypermethylation is found in nearly all prostate carcinomas and is
believed to be an early event in prostate carcinogenesis. We
hypothesized that suppressed GSTP1 expression in prostate cells would
increase their vulnerability to cytotoxicity and DNA adduct formation
mediated by activated PhIP metabolites. To test this hypothesis, the
human prostate adenocarcinoma cell line, LNCaP, which contains a
silenced GSTP1 gene, was genetically modified to
constitutively express high levels of GSTP1. Both LNCaP and LNCaP-GSTP1
cells exposed to N-OH-PhIP, but not parent PhIP, for
24 h showed a dose-dependent decrease in cell viability.
GSTP1-overexpressing cells had LC50s 30–40% higher than
cells transfected with the vector alone. PhIP-DNA adducts isolated from
LNCaP-derived cells and primary human prostate tissue cultures exposed
to N-OH-PhIP were analyzed by liquid
chromatography/electrospray ionization mass spectrometry. Primary
cultures of human prostate tissue and LNCaP-GSTP1 cells had 
50%
lower adduct levels than parental LNCaP and vector control cells.
Bioactivation assays using LNCaP cytosols showed that enzymatic
activation of N-OH-PhIP to a DNA binding species was
dependent on ATP and could be inhibited by recombinant human GSTP1 in
the presence of glutathione. This evidence confirms that
N-OH-PhIP can be bioactivated to a DNA binding species
in human prostate and human prostate-derived cells. These observations
provide the basis for using LNCaP and LNCaP-GSTP1 cells as a model
system for studying the role of this enzyme in protection against
N-OH-PhIP induced DNA damage in prostate carcinogenesis.
Loss of GSTP1 expression in human prostate may, therefore, enhance its
susceptibility to carcinogenic insult by compounds such as
N-OH-PhIP. Conversely, induction of GSTs in early-stage
prostate carcinogenesis may be a useful protective strategy.
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