2 research outputs found
Effects of Black Raspberry Extract and Berry Compounds on Repair of DNA Damage and Mutagenesis Induced by Chemical and Physical Agents in Human Oral Leukoplakia and Rat Oral Fibroblasts
Black
raspberries (BRB) have been shown to inhibit carcinogenesis
in a number of systems, with most studies focusing on progression.
Previously we reported that an anthocyanin-enriched black raspberry
extract (BE) enhanced repair of dibenzo-[<i>a,l</i>]-pyrene
dihydrodiol (DBP-diol)-induced DNA adducts and inhibited DBP-diol
and DBP-diolepoxide (DBPDE)-induced mutagenesis in a <i>lacI</i> rat oral fibroblast cell line, suggesting a role for BRB in the
inhibition of initiation of carcinogenesis. Here we extend this work
to protection by BE against DNA adduct formation induced by dibenzo-[<i>a,l</i>]-pyrene (DBP) in a human oral leukoplakia cell line (MSK)
and to a second carcinogen, UV light. Treatment of MSK cells with
DBP and DBPDE led to a dose-dependent increase in DBP-DNA adducts.
Treatment of MSK cells with BE after addition of DBP reduced levels
of adducts relative to cells treated with DBP alone, and treatment
of rat oral fibroblasts with BE after addition of DBPDE inhibited
mutagenesis. These observations showed that BE affected repair of
DNA adducts and not metabolism of DBP. As a proof of principle we
also tested aglycones of two anthocyanins commonly found in berries,
delphinidin chloride and pelargonidin chloride. Delphinidin chloride
reduced DBP-DNA adduct levels in MSK cells, while PGA did not. These
results suggested that certain anthocyanins can enhance repair of
bulky DNA adducts. As DBP and its metabolites induced formation of
bulky DNA adducts, we investigated the effects of BE on genotoxic
effects of a second carcinogen that induces bulky DNA damage, UV light.
UV irradiation produced a dose-dependent increase in cyclobutanepyrimidine
dimer levels in MSK cells, and post-UV treatment with BE resulted
in lower cyclobutanepyrimidine dimer levels. Post-UV treatment of
the rat <i>lacI</i> cells with BE reduced UV-induced mutagenesis.
Taken together, the results demonstrate that BE extract reduces bulky
DNA damage and mutagenesis and support a role for BRB in the inhibition
of initiation of carcinogenesis
Mechanisms Underlying the Varied Mammary Carcinogenicity of the Environmental Pollutant 6‑Nitrochrysene and Its Metabolites (−)‑[<i>R</i>,<i>R</i>]- and (+)‑[<i>S</i>,<i>S</i>]‑1,2-Dihydroxy-1,2-dihydro-6-nitrochrysene in the Rat
The
mechanisms that can account for the remarkable mammary carcinogenicity
of the environmental pollutant 6-nitrochrysene (6-NC) in the rat remain
elusive. In our previous studies, we identified several 6-NC-derived
DNA adducts in the rat mammary gland; one major adduct was derived
from (±)-<i>trans</i>-1,2-dihydroxy-1,2-dihydro-6-nitrochrysene
(1,2-DHD-6-NC). In the present study, we resolved the racemic (±)-1,2-DHD-6-NC
into (−)-[<i>R</i>,<i>R</i>]- and (+)-[<i>S</i>,<i>S</i>]-1,2-DHD-6-NC and compared their <i>in vivo</i> mutagenicity and carcinogenicity in the mammary
glands of female transgenic (BigBlue F344 × Sprague–Dawley)ÂF1
rats harboring <i>lacI</i>/<i>cII</i> and Sprague–Dawley
rats, respectively. Both [<i>R</i>,<i>R</i>]-
and [<i>S</i>,<i>S</i>]-isomers exerted similar
mutagenicity and carcinogenicity but were less potent than 6-NC. Additional <i>in vivo</i> and <i>in vitro</i> studies were then
performed to explore possible mechanisms that can explain the higher
potency of 6-NC than 1,2-DHD-6-NC. Using ELISA, we found that neither
6-NC nor 1,2-DHD-6-NC increased the levels of several inflammatory
cytokines in plasma obtained from rats 24 h after treatment. In MCF-7
cells, as determined by immunoblotting, the effects of 6-NC and 1,2-DHD-6-NC
on protein expression (p53, Akt, p38, JNK, c-myc, bcl-2, PCNA, and
ERβ) were comparable; however, the expressions of AhR and ERα
proteins were decreased by 6-NC but not 1,2-DHD-6-NC. The expression
of both receptors was decreased in mammary tissues of rats treated
with 6-NC. Our findings suggest that the differential effects of 6-NC
and 1,2-DHD-6-NC on AhR and ERα could potentially account for
the higher carcinogenicity of 6-NC in the rat mammary gland