Biomedical Engineering Reference
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humans and squamous cell carcinomas of the respiratory epithelium of
rats and mice (Kerns et al., 1983; IARC, 2006), but this species is
rapidly metabolized by ADH3 to FA, and increases in formaldehyde
levels were not observed in body fluids or tissues following acute high-
dose MeOH exposures in early studies with formaldehyde detection
limits of 25
M (Makar and Tephly, 1977; McMartin et al., 1977;
McMartin et al., 1979). Formaldehyde is a metabolic intermediate
endogenously produced from amino acid metabolism and exists at
concentrations of about 0.1mM in human blood (IARC, 2006). In
addition to rapid metabolism to FA, formaldehyde can be sequestered as
macromolecular adducts to endogenous nucleophiles such as DNA,
lipid, and protein. Recent formaldehyde inhalation studies using radio-
labeled formaldehyde reported that exogenous formaldehyde DNA
adducts were observed only in nasal DNA, and that the exogenous
adduct levels did not exceed the levels of endogenous formaldehyde
DNA adducts, suggesting that additional mechanism(s) in addition to
DNA adduct formation are involved in formaldehyde-dependent naso-
pharyngeal cancer (Lu et al., 2010; Moeller et al., 2011). Exposure of
Sprague-Dawley rats to MeOH (20,000 ppm) or formaldehyde
(1500 ppm) in drinking water for 7 days failed to increase the basal
levels of the major formaldehyde-DNA adduct N 6 -hydroxymethyldeox-
yadenosine (N 6 -HOMe-dAdo) in leukocyte or hepatocyte DNA (Wang
et al., 2008). Another potential indirect mechanism of MeOH-initiated
carcinogenesis is via ROS-mediated oxidative damage to DNA. MeOH
could promote ROS formation directly via a free radical intermediate,
or indirectly via mechanisms including the activation and/or enhance-
ment of ROS-producing NADPH oxidases (NOXs), as has been
reported for EtOH (Dong et al., 2010). Several studies have reported
free radical production during MeOH biotransformation (Skrzydlewska
et al., 2000; Castro et al., 2002; Paula et al., 2003), with the most direct
evidence being the direct detection of a -(4-pyridyl-1-oxide)-N-tert-
butylnitrone (POBN)-hydroxymethyl radical adducts in bile and urine
from rats acutely intoxicated with MeOH (Kadiiska and Mason, 2000).
Oxidatively damaged DNA has been implicated for decades as a
causal factor in carcinogenesis (Ames, 1989), the most commonly
measured lesion being 8-hydroxyguanine, or
m
its physiologically
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