Chemistry Reference
In-Depth Information
Besides direct and indirect interaction with repair or repair-associated proteins,
arsenic compounds may also diminish DNA repair by altering the expression of
specifi c DNA repair genes. Thus Hamadeh
et al.
136
and Andrew
et al.
137
reported a
decreased gene expression of various repair genes in arsenite-exposed human
normal keratinocytes and cultured human bronchial epithelial cells, respectively.
Our recent work demonstrates that arsenite strongly decreased expression and
protein level of XPC, which is believed to be the principle initiator of global genome
NER. This phenomenon was even more pronounced with MMA
III
. This led to
diminished association of XPC to sites of local UVC damage in human fi broblasts,
resulting in decreased recruitment of further NER proteins and therefore disrupted
DNA repair.
138
In humans, arsenic exposure via drinking water was correlated in a dose-
dependent manner to decreased expression of NER and BER genes and diminished
repair of lesions in lymphocytes.
139,140
Additionally, a recent study showed that upon
induction of DNA damage by gamma irradiation, the repair capacity in whole blood
of arsenic-exposed individuals with premalignant hyperkeratosis was signifi cantly
less, compared to that of individuals without skin lesions.
141
Table 18.2 summarizes
studies providing evidence for inhibition of nucleotide and base excision repair by
inorganic and methylated arsenicals.
18.5 Conclusions and Research Needs
Taken together, the carcinogenicity of inorganic arsenic is well documented, but
underlying mechanisms are not completely understood. Current evidence suggests
that indirect mechanisms play a predominant role: rather than direct binding to
DNA, interactions with proteins are of major importance, leading to oxidative stress
and modulating the cellular response to DNA damage, which may in turn decrease
genomic integrity (Figure 18.2). This would also explain the enhancement of
benzo[a]pyrene and UV-induced carcinogenicity in animals and exposed humans,
which may be due to the disturbance of DNA repair processes. However, in spite
of many advances in arsenic-related toxicology, several aspects need to be addressed
in future research. They include further insights into arsenic metabolism in humans
and the relevance of metabolites in arsenic-induced genotoxicity and carcinogenic-
ity. Furthermore, the impact of genetic polymorphisms, both in arsenic biomethyla-
tion and in DNA repair genes, needs to be clarifi ed. Finally, the toxicological impact
of organic arsenic compounds such as arsenosugars and arsenolipids warrants special
attention.
Acknowledgements
This work was supported by the DFG grant number Ha 2372/3-4 and SCHW
903/3 - 2.
