Chemistry Reference
In-Depth Information
35, 68 and 69). Thus, in diverse cellular systems, arsenite increases the generation of
superoxide anions (
i
O
−
) and hydrogen peroxide (H
2
O
2
), and modulates the level of
nitric oxide (NO). Subsequently these reactive species can be converted to other,
more damaging reactive species, such as the hydroxyl radical (
·
OH) and peroxyni-
trite (ONOO
−
). Several origins of elevated levels of reactive species have been
suggested. They include interactions with the respiratory chain,
70,71
their generation
during metabolism of inorganic arsenic, such as the formation of intermediary
dimethylarsine and radical arsenic species,
72 - 79
the release of iron from ferritin
by dimethylated arsenic species,
80,81
and modulation of NO synthases.
31,68,82
All
of these mechanisms may lead to oxidative stress, resulting from an imbalance
between free radical generation and cellular antioxidant defence systems.
83
Moreo-
ver, arsenic has not only been shown to increase the generation of reactive species,
but also to interact with cellular protection mechanisms. Thus arsenic is believed
to change cellular redox homeostasis by decreasing cellular GSH. This might be
due to the ability of trivalent arsenicals to complex with thiol groups, resulting in
GSH binding and depletion, consumption of GSH during arsenic metabolism, as
well as effects of trivalent methylated arsenicals on glutathione-related enzymes.
84,85
With respect to genotoxicity, the application of radical scavengers revealed the
involvement of arsenite-induced ROS and RNS in the induction of lipid peroxida-
tion, protein oxidation, DNA damage (summarized in reference 35) and DNA
repair inhibition.
86
Furthermore chronic low-dose arsenic alters gene expression and
protein levels that are associated with oxidative stress and infl ammation (e.g.,
references 87-89), which may in part be due to oxidation of major transcriptional
redox sensitive regulators (e.g., Nrf2, nuclear factor-erythroid 2-related factor 2) of
altered genes. Thus the induced reactive species are known to activate signal cas-
cades such as the mitogen-activated protein kinases (MAPKs) cascade and the
transcription factors AP-1 (activator protein-1) and NFk B (nuclear factor - k B)
(summarized in references 31 and 90). Finally, the fact that arsenite-induced oxi-
dative stress is also evident in populations exposed to arsenic-contaminated drink-
ing water underscores its role in arsenic-induced carcinogenicity (see, for example,
references 91 - 97 ).
18.4.3 Epigenetic Effects
In addition to the induction of genetic damage, altered DNA methylation may also
contribute to carcinogenicity. Thus, in tumours global methylation is typically
reduced, but some gene-specifi c promoter methylation is increased, thereby affect-
ing the expression of protooncogenes and tumour suppressor genes, resulting in cell
transformation and upregulated cell growth.
98,99
Over the last 10 years accumulating
evidence from cell culture studies, experimental animals and also from arsenic-
exposed humans suggests that epigenetic changes contribute to arsenic-induced
carcinogenicity. Thus both hypo- and hypermethylation have been observed after
arsenic exposure. For instance, increased cytosine methylation in the p53 promoter
was detected in A549 human lung cells by arsenite and arsenate, but not by DMA
v
100
