Chemistry Reference
In-Depth Information
studies have shown that they are as toxic, or even more toxic, compared to inorganic
arsenic. Thus, with respect to molecular mechanisms, special emphasis is given to
the biomethylated arsenicals, as they may at least contribute to inorganic arsenic-
induced genotoxicity and presumably carcinogenicity (reviewed in references 30-
33). Whereas the ability of arsenic to induce carcinogenicity is beyond dispute, the
mechanisms of how arsenic induces cancer in humans have not been clearly
identifi ed. Various modes of action have been proposed to be involved, which are
discussed based on recent reviews
22,26,30,32,34 - 37
and numerous original papers. Since
evidence of inorganic arsenic-induced carcinogenicity in laboratory animals is
mostly negative, modes of action studies are mostly conducted in cell culture
systems.
18.4 Modes of Action
18.4.1 Induction of Genetic Damage
Unlike many other carcinogens, arsenite neither directly interacts with DNA nor
induces point mutations in bacterial or mammalian test systems (reviewed in refer-
ences 4 and 10). However, arsenite has been shown to induce large deletion (multi-
locus) mutations in hamster human hybrid cells,
38
micronuclei (MN) and chromosomal
aberrations (CA), aneuploidy and sister-chromatid exchanges (SCE) in various
mammalian cells (recently summarized in reference 2). Also in peripheral
lymphocytes, oral mucosa or bladder urothelial cells of humans exposed towards
elevated levels of arsenic in drinking water, numerous studies observed increases
in chromosomal aberrations, micronuclei and sister chromatid exchanges
(Table 18.1 ).
In vitro
studies in mammalian cells demonstrated the induction of DNA damage
(strand breaks, oxidative base modifi cations, apurinic/apyrimidinic sites, DNA-
protein crosslinks) and inhibition of DNA repair (see below). Thus, chromosomal
alterations may be a secondary result of arsenite-induced DNA damage and DNA
repair inhibition.
32
Furthermore Li and Broome proposed a model, in which arsenite
crosslinks tubulin and inhibits GTP binding, resulting in disturbed tubulin polym-
erization and mitosis,
39
which may contribute to micronuclei formation. Addition-
ally, arsenite and arsenate can cause gene amplifi cation in mouse 3T6 cells.
40
Since
oncogenes are amplifi ed in several animal and human tumours, the ability of arsenic
to induce gene amplifi cation may relate to its carcinogenic effects.
Regarding the methylated species, MMA
III
and DMA
III
are generally genotoxic
at lower concentrations than inorganic arsenic, while effects of the pentavalent
metabolites MMA
V
and DMA
V
are either absent or restricted to much higher con-
centrations (e.g., references 41-45). In this context Kligermann and coworkers have
recently summarized evidence that trivalent methylated arsenicals are potent clas-
togens and, due to spindle disruption, are aneugens as well.
32
While arsenic is not a classical mutagen, it increases the genotoxicity, muta-
genicity and clastogenicity of other DNA damaging agents, among others UV light,
