Chemistry Reference
In-Depth Information
responsible for lesion formation.
30 - 32
Perhaps more interesting is current research
suggesting that ascorbate, classically thought of as an antioxidant, may serve as a
pro-oxidant with regard to intracellular metabolism of Cr(VI).
33
There is also recent
evidence that ascorbate-ligated high-valent chromium species may have multiple
roles in both oxidative DNA damage and in the formation of Cr-DNA adducts, as
detailed in later sections of this review.
C r ( VI ) Reactions with Glutathione
Glutathione, a tripeptide of g -glutamylcysteinylglycine, is likely to be another major
player in the intracellular reduction of Cr(VI). Reduction of Cr(VI) in the presence
of glutathione is signifi cantly slower than that observed with ascorbate, but glutath-
ione is generally present in cells at considerably higher (millimolar) levels than
ascorbate.
34
A number of reactive intermediates have been associated with the
Cr(VI) metabolism process by glutathione.
35 - 37
Among these are the glutathionyl
radical (Figure 17.2;
VI
), which may react with molecular oxygen to produce
the superoxide anion
38
(Figure 17.2 ;
V
). Similar to the reactions observed with
ascorbate metabolism of Cr(VI), glutathione metabolism of this metal also forms
high-valent Cr(V) species (Figure 17.3B) that have been observed by electron spin
resonance spectroscopy, ESR.
35,36
Once again, the ultimate species that may be
responsible for DNA damage during the glutathione-dependent metabolism process
is unknown. Much like ascorbate, glutathione's normal role of maintaining cellular
redox homeostasis may be altered to one of a pro-oxidant with regard to Cr(VI)
metabolism.
C r ( VI ) Reactions with Hydrogen Peroxide
The reactions of Cr(VI) with hydrogen peroxide have been extensively studied,
although this may be due more to the ability of this reaction to induce signifi cant
DNA modifi cations than with any cellular reality. Hydrogen peroxide is highly reac-
tive with metal species and as such is kept at very low levels in the cell, which would
seem to preclude any signifi cant metabolic reduction of Cr(VI) by this species.
39,40
However, a case could be made for reactions of this nature in the mitochondria
where a steady-state level of hydrogen peroxide is produced during respiration
accounting for up to 5% of total cellular oxygen consumption.
41
In general, the
reaction of Cr(VI) with hydrogen peroxide generates the classical reactive oxygen
species, ROS, that have been observed with the Fenton metals of iron and copper.
These include singlet oxygen, the hydroxyl radical and the superoxide anion (Figure
17.2 ;
III
,
IV
and
V
respectively).
42,43
A high - valent Cr(V) tetraperoxochromate
species (Figure 17.3C) has also been observed by ESR that is highly reactive with
DNA.
44
This species is only formed in extremely alkaline solutions and is probably
not physiologically relevant. The DNA reactivity of ROS species have been exten-
sively reviewed elsewhere and will not be discussed to any length in this review.
However, it should be noted that many of the same DNA lesions formed by these
classical ROS are now being found to arise from a direct or metal-mediated type
of oxidation reaction with DNA.
