Chemistry Reference
In-Depth Information
(further effects on p53 are discussed below). After exposure of A549 human lung
and UOK human kidney cells to arsenite for several weeks, Zhong and Mass
observed both hypo- and hypermethylation of different genes,
101
whereas in a rat
liver cell line
102
and human HaCaT keratinocytes
103
global DNA hypomethylation
was found following chronic exposure to low levels of arsenite. In A/J mice, which
were chronically orally exposed to arsenate and developed lung tumours, hyper-
methylation was observed with the consequence of diminished p16
INK4a
and
RASSF1A expression occurring in these tumours.
104
With respect to humans, dose-
dependent hypermethylation of the p53 and p16 genes was observed in blood
samples of arsenic-exposed skin cancer patients in West Bengal.
105
Additionally, in
a population-based study of human bladder cancer, arsenic exposure measured as
toenail arsenic was associated with promoter hypermethylation of the tumour sup-
pressor proteins RASSF1A and PRSS3, but not p16
INK4a
.
106
While hypomethylation
may be due to inhibition of DNA methyltransferases or depletion of the methyl
donor SAM,
102,103
which is a common cofactor in DNA and arsenic methylation,
hypermethylation is not easily understood and further studies are required to
resolve this question.
18.4.4 Inhibition of DNA Repair
To ensure faithful duplication and inheritance of genetic material, organisms have
evolved to effi ciently detect and remove DNA damage resulting from either endog-
enous sources (cellular metabolic processes) or exogenous sources (environmental
factors). Dysregulation of DNA damage-response processes, including cell cycle
arrest, DNA repair, senescence or apoptosis, contribute to genomic instability on
the cellular level, predisposing the organism to cancer.
107
Therefore, it is absolutely
essential for cells to effi ciently respond to DNA damage through coordinated and
integrated cell cycle checkpoints and DNA repair pathways.
108 - 110
Concerning DNA
repair inhibition as one underlying mechanism of arsenic-induced carcinogenicity,
several studies point to an interaction of arsenic with various DNA repair pathways,
including nucleotide (NER) and base excision repair (BER) (reviewed in references
30 and 34 ).
NER is capable of removing a wide variety of bulky, DNA-helix-distorting
lesions, caused by UV radiation, chemotherapeutic drugs or environmental
mutagens. During the last few years there has been accumulating evidence that
low, noncytotoxic concentrations of arsenite inhibit nucleotide excision repair
(NER),
47,86,111 - 115
which is even more pronounced with the trivalent methylated
metabolites MMA
III
and DMA
III
.
42,116
Thus, arsenic has been shown to decrease
removal of bulky DNA adducts induced by UV radiation
47,86,111 - 113,115
or benzo[
a
]pyrene
in cultured cells and laboratory animals.
42,114,116,117
NER works through a ' cut - and -
patch' mechanism; after DNA damage recognition, incisions at sites fl anking the
lesion occur and an oligonucleotide (24-32 nucleotides) containing the lesion is
excised, followed by subsequent restoration of the original DNA sequence by
polymerisation/ligation using the nondamaged strand as a template. In total, about
