Chemistry Reference
In-Depth Information
O
O
O
L
x
Cr
n-2
N
H
N
N
NH
NH
L
x
Cr
n
NH
O
L
x
Cr
n
O
O
N
R
N
R
NH
2
N
R
N
NH
2
N
NH
2
N
Guanine
8-oxoG
Figure 17.5
Two-electron oxidation mechanism that gives rise to 8-oxoG
High-valent metal species such as those observed to arise from Cr(VI) reduc-
tion (Figure 17.3) have the potential to generate the same 8-oxoG lesion, but
through a different mechanism than that of the single-electron oxidation shown in
Figure 17.4. This mechanism involves the transfer of the axial oxo atom (a two-
electron oxidation mechanism) of the Cr(V) or Cr(IV) complex to the substrate
through a discrete innersphere interaction (Figure 17.5). While this mechanism has
yet to be shown to form 8-oxoG from guanine, it has been shown to occur for a
number of other substrates.
62,63
Validation of this mechanism is possible using iso-
topically labelled oxygen in the oxo-atom-containing chromium complex, but is
problematic due to the rapid exchange of the oxo-atom with the surrounding water.
62
However, a similar mechanism for 8-oxoG formation has been observed with high-
valent ruthenium - oxo complexes.
64
For years 8-oxoG was considered the terminal (and most relevant) oxidation
product of guanine in DNA. However, the reduction potential of 8-oxoG is consid-
erably lower than that of the parent guanine residue (Table 17.1) making it a prime
target for further oxidative events. While it may seem unlikely for two discrete oxi-
dative events to occur at the same DNA base (without some sort of a cage effect)
recent studies have shown the formation of further oxidized products of 8-oxoG
both
in vitro
65
and in cellular systems.
66
A mechanism referred to as charge transfer
has been proposed to explain this effect. When an oxidative event occurs at one
base in a DNA sequence it can be translated through the DNA to an electron sink
- a nucleoside with a lower reduction potential than the neighbouring nucleosides.
67
The stacked bases in B-form DNA create an array of overlapping
- orbitals that
facilitate charge transfer through the DNA sequence.
68
8-OxoG lesions can act as a
sink for charge transfer because of their lowered reduction potential relative to that
of the four undamaged nucleosides. When an 8-oxoG lesion is present within
approximately 10-20 base pairs (presumably from an initial oxidative insult and
greatly dependent on the DNA sequence)
68
of the site of a secondary electron
abstraction from a nucleobase, the resultant charge can be transferred to an 8-oxoG
residue, causing a further oxidative event at that lesion.
The low reduction potential of 8-oxoG combined with its ability to act as a sink
for charge transfer in a DNA sequence suggests that 8-oxoG is not likely to be the
end product of an oxidative attack on the nucleobases. One of the further oxidized
lesions that has been shown to form both
in vitro
65
and in cellular systems
66
is
spiroiminodihydantoin (Sp). Sp lesions can be generated by a single electron abstrac-
tion from 8 - oxoG (Figure 17.6 ),
65
which can be achieved by both Cr(V) and Cr(IV)
π
