Biomedical Engineering Reference
In-Depth Information
substantially more embryotoxic in embryo culture than MeOH itself or
its stable formate metabolite (Hansen et al., 2005). Additionally, as yet
undetermined effects of MeOH itself have been postulated to initiate
teratogenesis (NTP, 2002). Although formaldehyde remains a candidate
for the proximate toxic chemical species due to its high embryotoxic
potency in embryo culture (Hansen et al., 2005), the physiological
relevance of treating embryos with this reactive metabolite, as distinct
from having it produced metabolically within the embryo, remains
unclear. However, the lower levels of embryonic formaldehyde
dehydrogenase (ADH3) levels in mice compared to rats (Harris
et al., 2003) may explain the greater susceptibility of mice to MeOH
teratogenesis, consistent with a role for formaldehyde as the proximate
chemical teratogen. The acute ocular toxicity and lethality observed in
humans poisoned with MeOH appear to be due to metabolic acidosis
initiated by high concentrations of the FA metabolite, which appears
not
to play a role in the developmental
toxicity of MeOH (see
Section 7.3.1).
Our studies on the role of ROS in MeOH developmental toxicity are
discussed later in Section 7.4.
7.1.5 Factors Affecting the Human Relevance of Animal
Models
7.1.5.1 Species Differences in Metabolism Primates, including
humans, use alcohol dehydrogenase (ADH1) to oxidize MeOH to
formaldehyde, whereas rodents use the peroxidative activity of catalase
(Tephly et al., 1964; Makar et al., 1968; Cederbaum and Qureshi, 1982)
(Figure 7.1). Both humans and rodents convert formaldehyde into
formic acid (FA) by ADH3 (Teng et al., 2001; Harris et al., 2004).
FA is subsequently metabolized into carbon dioxide and water by a
folate-dependent dehydrogenase (Johlin et al., 1987). Folate, however,
is limited in humans, leading to an accumulation of the toxic FA
metabolite following exposure to high levels of MeOH (Perkins
et al., 1995). Conversely, folate is not limited in rodents (Black
et al., 1985), and a combined use of the peroxidative activity of catalase
and the aforementioned folate-dependent pathway prevents
the
