Chemistry Reference
In-Depth Information
O
O
L
L
R
R
LL
N
N
Cr
NH
NH
L
Cr
O
P
O
O
P
O
L
L
N
N
LL
NH
2
N
NH
2
O
N
O
O
O
H
H
H
H
H
H
H
H
b
a
H
H
R
R
H
L
O
O
LL
H
O
H
L
R
L
Cr
O
H
Cr
N
R
N
NH
NH
O
P
O
L
L
O
P
O
N
NH
2
O
N
N
NH
2
N
O
O
O
H
H
H
H
H
H
H
H
c
H
R
R
H
d
Figure 17.11
Proposed structures for covalent Cr(III)-DNA bound binary and ternary
adducts
100,102
associated with the DNA was chelatable with EDTA indicating that it was likely
covalently bound.
101,102
It should be noted, however, that no detailed structure has
yet shown the veracity of these adducts. The ability of chromium to covalently bind
to DNA would allow for the formation of chromium-mediated DNA-DNA and
protein-DNA crosslinks that have been proposed to arise in Cr(VI)-treated cellular
systems. This will be discussed in more detailed in subsequent sections.
17.4.2 MMR Repair and Toxicity Associated with Chromium - DNA Adducts
Recent studies have indicated that the small ternary chromium-DNA adducts pro-
posed in Figures 17.11b and d are recognized and repaired by the mismatch repair
(MMR) system.
103
Inactivating any of the four major MMR proteins (MSH6, MSH2,
MLH1, PMS2) from human or mouse cells creates a Cr(VI) resistant phenotype.
103,104
Cells profi cient in MMR should undergo apoptosis following exposure to low doses
of Cr(VI), as MMR plays a role in both repair and controlled cellular toxicity.
103
MMR is proposed to recognize DNA bending caused by Cr-DNA adducts
105
and then cleave a segment of DNA - up to 1000 base pairs - surrounding these
adducts.
106 - 108
This repair process is now thought to act as a signal for the activation
of cell cycle arrest and eventually apoptosis by creating single-strand breaks,
93
which
are manifested into double-strand breaks following a round of replication.
107
Because
a round of replication is required before the double-strand breaks will be mani-
fested, MMR-induced double-strand breaks appear most frequently in the G2 phase
of the cell cycle.
102,107
The ability of MMR to trigger G2 cell cycle arrest as well as
