Chemistry Reference
In-Depth Information
O
O
O
N
N
N
- e
-
- H
+
- e
-
NH
NH
N
O
O
O
R
R
R
N
NH
2
N
NH
2
N
NH
2
8-oxoG
H
2
O
H
O
OO
O
N
HN
NH
N
acyl shift
O
R
H
R
NH
N
NH
2
O
Spiroiminodihydantoin, Sp
5-OH-8-oxoG
Figure 17.6
Single-electron oxidation mechanism of 8-oxoG to give the Sp lesion
65
intermediates during reduction by ascorbate. In this mechanism, the initial one-
electron abstraction forms an 8-oxoG radical cation intermediate that is a substrate
for nucleophilic addition of water to form the 5-hydroxy-8-oxoG intermediate that
undergoes rearrangement via an acyl shift to give Sp (Figure 17.6). It should be
noted that while the overall reaction is a two-electron oxidation, the mechanism
invokes two discrete one-electron abstraction processes.
Recently, an alternative mechanism has been proposed for the formation of the
further oxidized product Sp from 8-oxoG.
69
This mechanism is similar to that for
the formation of 8-oxoG from guanine through the oxo atom transfer mechanism
proposed in Figure 17.5. In this mechanism, an inner-sphere oxidation complex is
formed with the 8-oxoG lesion, resulting in transfer of the oxo atom from the Cr(V)
species to the C5 of 8-oxoG (Figure 17.7).
69
This mechanism was confi rmed using
isotopic labelling, although it is still unclear whether it is viable in cellular systems
since it would require a direct interaction between the chromium complex and the
8 - oxoG lesion.
The formation of Sp helps to explain the high level of mutations, and the
varying types of mutations, observed in Cr(VI) treated systems, that cannot be
accounted for by the formation of 8-oxoG lesions alone. Sp, like 8-oxoG, can produce
G:C
T:A transversion mutations, but at a much higher level than 8-oxoG. In addi-
tion to the G:C
→
C:G trans-
version mutations and polymerase arrest both
in vitro
and in cellular systems.
70 - 72
There are potentially a wide variety of nucleobase lesions that have the ability to
be formed from multiple chromium-induced oxidation events at guanine in DNA.
8-OxoG and Sp are the only two that have been observed in cellular systems and
as such are the main focus in this part of the review. A lesion similar to Sp, guanidi-
nohydantoin (Gh), has been shown to form with Cr(V) treatment
in vitro
from the
8 - oxoG nucleoside,
73,74
but has yet to be identifi ed as arising in cellular systems.
Figure 17.8 shows a more comprehensive picture of the wide variety of nucleobase
→
T:A transversion mutations, Sp can also produce G:C
→
