Chemistry Reference
In-Depth Information
cell is much lower than 1 mM,
56
indicating that oxidation of nucleic acids by ROS
is likely to play a small role in the overall nucleobase oxidative damage that has
been observed in cells exposed to Cr(VI). A second pathway that is thought to
account for the majority of nucleobase oxidation induced by Cr(VI) exposure
involves the direct abstraction of an electron from nucleic acids by the Cr(V) and/or
Cr(IV) intermediate species formed during Cr(VI) reduction.
57
The vast majority
of nucleobase oxidation observed during the Cr(VI) reduction process occurs at
guanine residues. Guanine is preferentially oxidized by ROS and by high-valent
chromium intermediates because of its lower one-electron reduction potential rela-
tive to that of the other three bases (Table 17.1).
58 - 60
The reduction potential becomes
even lower for 5
guanine residues when a run of consecutive guanine residues is
present in a DNA sequence (Table 17.1).
58 - 60
The most recognized lesion formed by
a single electron abstraction mechanism from a guanine residue is 7,8-dihydro-8-
oxo - 2
′
- deoxyguanosine (8 - oxoG) (Figure 17.4 ). In fact, 8 - oxoG is often viewed as
the primary genetic marker of oxidative stress
23
and if not repaired is mutagenic, as
8-oxoG can mispair with adenine during DNA replication leading to G:C
′
→
T:A
transversion mutations.
61
Table 17.1
Reduction potentials for nucleosides and nucleotide sequences
58-60
Nucleoside
a
E
(V vs NHE)
DNA Sequence
E
(V vs NHE)
Guanine (G)
1.29
GGG
0.64
Adenine (A)
1.42
GG
0.82
Cytosine (C)
1.6
GA
1.00
Thymine (T)
1.7
GC
1.15
8-oxoG
0.7
GT
1.16
a
The reduction as listed is for the radical cation of the corresponding nucleoside or nucleotide.
O
O
O
Cr
n
Cr
n-1
N
N
N
H
NH
OH
NH
NH
R
HO
R
R
N
NH
2
N
NH
2
N
NH
2
- e
-
- H
+
Guanine
O
N
NH
O
R
N
NH
2
8-oxoG
Figure 17.4
Sequential single electron oxidation mechanism of a guanine residue that gives
rise to the premutagenic 8-oxoG lesion
