Chemistry Reference
In-Depth Information
Those cells that are MMR defi cient will be apoptosis resistant following Cr(VI)
exposure. While the normal MMR profi cient cells undergo apoptosis, the now initi-
ated MMR - defi cient cells will continue to grow and divide creating a population of
cells that harbour a host of genetic mutations. To date, these studies are the most
complete that show a correlation between chromium adduct formation, the role of
DNA repair and the downstream cellular effects that can lead to cancer
formation.
17.5 C r ( VI ) - Induced DNA Crosslinks
17.5.1 Formation of Crosslinks
As mentioned earlier, another class of lesions that can form following exposure of
DNA to high-valent chromium species are crosslinks. Crosslinking can occur between
DNA and a protein, between two adjacent sites on the same DNA strand (intras-
trand crosslink) or between neighbouring DNA strands (interstrand crosslink).
Small amounts of chromium can covalently bind to DNA through interactions with
the phosphate backbone
116,117
and form ternary adducts as described above.
100,102
Chromium(III)-mediated ternary adducts may also involve a linkage between the
phosphate backbone and protein, or with adjacent or opposite N7 groups of guanine
residues. These lesions would be the chromium-mediated protein and DNA
crosslinks. Since the DNA phosphate backbone is a fairly weak ligand, crosslink
formation involving covalently bound chromium atoms cannot fully explain the
extensive formation of crosslinks observed in many chromium-treated systems.
These type of coordinative adducts are the least well defi ned and, once again, no
structural characterization have been carried out on these systems.
An alternative proposal to explain the formation of protein and DNA crosslinks
is an oxidative pathway. Formation of single-strand breaks due to deoxyribose oxi-
dation
57,88
and accumulation of 8-oxoG and Sp due to guanine oxidation
82
following
Cr(VI) exposure demonstrate that chromium can be a powerful DNA oxidant.
Oxidation of the guanine residue, as well as the 8-oxoG residue, forms a radical
cation, as depicted in Figures 17.4 and 17.6. The radical cation presents an excellent
site for nucleophilic attack and, although water is not a strong nucleophile, the vast
amounts of water present surrounding the DNA favours the formation of lesions
such as 8-oxoG and Sp. A number of much better nucleophiles are also present
around the DNA, but are substantially less abundant than water. These include
amino acids, such as histidine and cysteine, either as small peptides or within com-
plete proteins, as well as the phosphate backbone of neighbouring DNA strands.
When these strong nucleophiles are in close proximity to a chromium-generated
radical cation, they may out-compete water and a DNA adduct with that nucle-
ophile will be formed rather than an oxidized base.
69
Therefore, DNA - DNA and
protein-DNA crosslinks could be formed without the discrete coordination of a
chromium atom, but as a result of a single-electron oxidation induced by Cr(V) or
Cr(IV) ions (Figure 17.13). While no structural evidence for this type of reaction in
