Chemistry Reference
In-Depth Information
17.1.4 General Types of DNA Damage Associated with Chromate
A wide variety of genetic damage that may initiate cancer formation has been
observed following Cr(VI) exposure. This wide array of genetic damage has con-
founded the chromium research community and there is still little general consensus
on the mechanism(s) of DNA damage by Cr(VI), even though it is one of the most
extensively studied carcinogenic metals. This damage includes DNA base and sugar
oxidation, Cr-DNA adducts, DNA-protein crosslinks, DNA-DNA crosslinks and
DNA strand scission.
45
The downstream effects of these lesions, if not outright toxic-
ity, can be lesion accumulation, mutation and apoptosis resistance. Cells that do not
undergo apoptosis due to the accumulation of chromium-induced genetic damage
will develop gene mutations,
46
chromosomal aberrations
47,48
and sister chromatid
exchanges.
47 - 49
This genetic damage caused by hexavalent chromium exposure is of
considerable concern for both industrial chrome workers and the general popula-
tion. Even with improved industrial practices, some workers are still exposed to as
much as several hundred
g of Cr(VI) m
− 3
of air.
47
The general public is also at risk
due to environmental chromium pollution from a legacy of 150 years of often ill-
conceived landfi ll practices, as well as pollution stemming from the mining, smelting
and wood treatment industries. There are 719 active superfund sites in the United
States with chromium listed as at least one of the major contaminants present.
50
Automobile emissions and cigarette smoke are another source of nonoccupational
exposure to Cr(VI).
47
Understanding the mechanisms and types of chromium-
induced genotoxicity is essential for combating the effects of occupational and
environmental exposure to Cr(VI) compounds. The remainder of this review focuses
on specifi c types of DNA damage that Cr(VI) compounds are known to form, the
current knowledge of how endogenous repair processes play a role in the removal
of these adducts and, the induction of downstream cellular effects from these DNA-
damaging processes.
µ
17.2 Nucleobase Oxidation
17.2.1 C r ( VI ) - Induced Damage at DNA Nucleobases
Once Cr(VI) has been taken up by a cell, it is rapidly reduced.
25
The highly reactive,
metastable intermediate oxidation states of Cr(V) and Cr(IV) are created as Cr(VI)
is reduced to the more stable Cr(III).
51 - 53
This reduction scenario sets up two major
pathways that can lead to oxidation of the nucleobases. One pathway involves the
formation of radical species as detailed above, but with primary emphasis placed
on reactive oxygen species (ROS). Through Fenton-like reactions with H
2
O
2
, both
Cr(III)
53
and Cr(VI)
54,55
have been shown to be capable of producing hydroxyl radi-
cals that can attack the electron-rich aromatic rings of the nucleobases. The ROS
pathway is favourable in the presence of high concentrations of H
2
O
2
(0.5 mM -
27 mM),
53 - 55
which have been used for many
in vitro
studies. However as stated
previously, under normal physiological conditions the concentration of H
2
O
2
in a
