Biomedical Engineering Reference
In-Depth Information
antioxidants such as catalase, superoxide dismutase, GSH, and vitaminC,
which may be a cellular response to counteract the enhanced ROS
formation (Parthasarathy et al., 2006a, 2006b). In contrast, following
a longer duration of MeOH exposure, there was a decrease in enzymatic
and nonenzymatic antioxidants, which could reflect cellular membrane
and macromolecular damage due to excessive oxidative stress.
7.4.2.2 Mechanism of MeOH-Initiated ROS Formation The mecha-
nisms by which MeOH and/or its metabolites enhance ROS formation
are yet to be determined. Numerous studies have implicated free
radical-initiated, ROS-mediated involvement in the mechanism of
toxicity including (1) direct detection of a MeOH radical by electron
spin resonance spectrometry, and oxidative protein damage in MeOH
intoxicated rats (Skrzydlewska et al., 2000); (2) MeOH-derived adducts
to the free radical spin trapping agent, alpha-phenyl-N-tert-butylnitrone
(PBN), detected in bile and urine of PBN-pretreated, MeOH-exposed
rats (Kadiiska and Mason, 2000); and (3) MeOH embryopathies in rat
whole embryo culture are enhanced by the depletion of GSH (Harris
et al., 2004). Additionally, MeOH-initiated oxidative stress, as evi-
denced by the production of the lipid peroxidation product MDA, along
with increases in antioxidative enzyme activities, was observed in the
lymphoid organs of adult rats (Parthasarathy et al., 2006a). Although the
enzyme(s) catalyzing this reaction remain to be determined, PHSs do
not appear to contribute, as MeOH embryopathies are not blocked by
pretreatment with the PHS inhibitor acetylsalicylic acid (ASA) (Miller
and Wells, unpublished). CYP2E1 expression is negligible during the
embryonic period, and low compared to adult activity during the fetal
period, particularly in rodents (Vieira et al., 1996; Juchau et al., 1998;
Hines, 2008), so CYP2E1-mediated superoxide formation would
appear to be an unlikely mechanism for embryonic ROS formation,
at least in rodents. Preliminary studies suggest that MeOH and/or its
metabolites may activate and/or induce the expression of embryonic
NOXs that produce embryopathic ROS, as MeOH embryopathies are
reduced by pretreatment with the NOX inhibitor diphenyleneiodonium
(DPI) (Miller and Wells, unpublished). This would be consistent with
the NOX-dependent ROS mechanism previously reported for the
