Chemistry Reference
In-Depth Information
4.2 Mutagenicity and Genotoxicity of Nickel
Compounds
Ni compounds have been deemed human carcino-
gens by the International Agency for Research on Cancer
(IARC) (International Agency for Research on Cancer,
1990). Interestingly, these compounds are not very muta-
genic in most of the tested assay systems (Coogan
et al.
,
1989; Costa, 1991b; Costa
et al.
, 2002). Although, Ni com-
pounds are not mutagenic in cultured murine or human
fi broblasts, they do induce strong cell transformation, par-
ticularly in murine systems (Biedermann and Landolph,
1987; Miura
et al.
, 1989). Other studies have shown that
Ni compounds induce oxidative stress, genomic instabil-
ity, and chromosome damage (Biggart and Costa, 1986;
Conway and Costa, 1989; Costa
et al.
, 2002; Kargacin
et al.
,
1993; Kasprzak
et al.
, 2003; Lin
et al.
, 1991; Sen and Costa,
1985). Ni compounds have also been shown to cause cell
transformation accompanied by global deregulation of
gene expression (Landolph
et al.
, 2002; Verma
et al.
, 2004).
Perhaps one of the most important effects of Ni in terms
of affecting DNA is its ability to silence genes through
DNA methylation and other epigenetic effects (Klein and
Costa, 1997; Klein
et al.
, 1991). The epigenetic effects of
nickel compounds are more potent with the water-insol-
uble forms of Ni compounds such as Ni
3
S
2
, but this effect
is also evident when cells are exposed to soluble Ni com-
pounds for long periods of time (Costa, 1995; Lee
et al.
,
1995; Oller
et al.
, 1997). Ni compounds can also induce
oxidative stress
in vivo
(Coogan
et al.
, 1989; Doreswamy
et al.
, 2004; Kasprzak, 1995).
effects involves the inhibition of the repair of BaP DNA
adducts (Feng
et al.
, 2003; Hu
et al.
, 2004a). Chromate
exposure has been shown to induce oxidative stress in
cells, and these effects are greater with some insoluble
Cr compounds (Leonard
et al.
, 2004b; Martin
et al.
, 1998;
Shi and Dalal, 1994). Oxidative stress, the reduction of
Cr (VI) to Cr (III), and the binding of Cr (III) to DNA are
thought to be involved in its mutagenesis and genotox-
icity. The binding of Cr (III) to the DNA can yield a wide
variety of DNA lesions, including ternary complexes of
Cr (III) with its reducer (ascorbic acid or GSH), as well
as DNA-DNA crosslinks, DNA-protein crosslinks, sin-
gle-strand breaks, and formation of alkaline labile sites
(Cantoni and Costa, 1984; Coogan
et al.
, 1991; Costa, 1990;
1991a; Miller and Costa, 1989a; 1989b; Miller
et al.
, 1991;
Sugiyama
et al.
, 1986; 1987; Zhitkovich, 2005; Zhitkovich
et al.
, 1995).
4.4 Mutagenicity and Genotoxicity of Arsenic
IARC has determined that As and As compounds
are carcinogenic to humans. In general, As compounds
show poor genotoxicity and mutagenicity. Some stud-
ies have found evidence of DNA damage by arsen-
ite such as micronuclei formation (Liu and Huang,
1997; Schaumloffel and Gebel, 1998) and DNA protein
crosslinks (Gebel, 1998); however, others did not fi nd
DNA protein crosslink formation by arsenite (Costa
et al.
, 1997). As has not been found to be mutagenic
in bacteria and cultured mammalian cells (Rossman
et al.
, 1980). However, a very consistent effect of As
compounds is being a comutagen, possibly by inhibit-
ing the repair of DNA lesions produced by genotoxic
agents such as UV (Rossman, 1981a; 1981b; Rossman
et al.
, 1977; 1986). Additional studies that support the
comutagenic effects of As are those studies showing
that it is also a cocarcinogen (Rossman
et al.
, 2001; 2004).
In addition, As has been shown to inhibit the ligation
step of DNA repair and, thus, can interact with many
genotoxic insults (Hu
et al.
, 1998).
4.3 Mutagenicity and Genotoxicity
of Chromium Compounds
IARC (1990) concluded that hexavalent Cr com-
pounds are likely human carcinogens based on the
available data. Water-soluble chromate compounds
were tested for cell transformation, mutagenicity, and
chromosomal damage and were found to be very
active (Bianchi
et al.
, 1983; Biederman and Landolph,
1987; 1990; Patierno
et al.
, 1988). Analysis of the nature
of mutations in a 104-base pair segment of the HPGRT
gene exon 3 showed a selectivity in substitutions for
GC base pairs (Chen and Thilly, 1994). Treatment of a
shuttle plasmid
in vitro
with a Cr (VI) reduction system
with glutathione or cells containing the shuttle plasmid
yielded mutations predominantly at GC sites (Liu
et al.
,
1999). Cr is known to have a preference for binding to
the phosphate backbone of DNA and with positively
charged N7 of guanine (Voitkun
et al.
, 1998; Zhitkovich,
2005; Zhitkovich
et al.
, 1995). Chromate is also synergis-
tic with other organic carcinogens, such as those present
in cigarette smoke. One possible mechanism for these
4.5 Mutagenicity and Genotoxicity of Cd
IARC has determined that there is suffi cient sci-
entifi c evidence to classify cadmium and cadmium
compounds carcinogenic in humans. In general, Cd
compounds are weakly mutagenic in most assay sys-
tems (Filipic and Hei, 2004), but have been shown to
be genotoxic to Leydig cells of the testes (Yang
et al.
,
2003). The mechanism by which Cd may be genoto-
xic is by indirectly inducing oxidative stress in cells as
a result of its inhibition of antioxidant enzymes and
depletion of antioxidant molecules such as GSH (Stohs
et al.
, 2000). Cd has been reported to be very active in
