Biomedical Engineering Reference
In-Depth Information
can form exogenous formaldehyde hydroxymethyl DNA adducts in
various tissues in rats that suggests a possible genotoxic mechanism of
action. The relevance of this finding to human is unknown because of
the metabolic differences between rats and humans.
8.3.2 Oxidative Damage
The mechanism by which methanol causes toxicity in the developing
embryo and fetus or possible cancer in rodents is not clearlyunderstood, but
a primary or contributing factor may be enhanced “oxidative stress,” or
increased formation of highly reactive and potentially toxic forms of
oxygen termed “reactive oxygen species” (ROS). Oxidative stress and
damage occurs when the concentration of ROS generated within a cell or
tissue exceeds the antioxidant capacity of the cell or tissues. These ROS
include highly toxic “free radical” intermediates such as hydroxyl radical
that havebeenimplicated inanumber of humandiseasesanddrug toxicities
including nongenotoxic cancer, neurodegenerative diseases, athero-
sclerosis, and birth defects (Roberts et al., 2009). In addition, oxidative
damage has been suggested as playing a role in breast, liver, prostate,
leukemia, and lung cancer. Tobacco smoking inman, another carcinogenic
source ofROS, increases the oxidativeDNAdamage rate by 35-50%(Loft
and Poulsen, 1996). Oxidative stress can be an important part of both
initiation and promotion in the cancer process (dieldrin, acrylonitrile)
(Jiang et al., 1998; Klaunig et al., 1998; Klaunig and Kamendulis (2004)).
In living cells, ROS are formed continuously as a result of normal
metabolism, biochemical reactions, and external factors (chemical
exposure). Antioxidant defense systems may not be able to provide
complete protection from the effects of increased ROS. These effects
include oxidative DNA damage, which has been suggested as an
important factor in some carcinogenic responses. The most abundant
of these lesions, 8-oxo-7, 8-dihydro-2 0 -deoxyguanosine (8-oxodG), is
the most frequent marker of oxidative DNA damage. Human studies
support the notion of oxidative DNA damage as an important mutagenic
and apparently carcinogenic factor. In addition, oxidative damage may
be important for the aging process, and the pathogenesis of inflamma-
tory diseases (Roberts et al., 2009).
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