Biomedical Engineering Reference
In-Depth Information
accumulation of the acutely toxic FA (Cook et al., 2001; Clary, 2003;
Harris et al., 2004). Accordingly, the metabolism of MeOH in rodents
does not reflect that in humans.
Despite these differences in metabolic pathways, the rate of MeOH
metabolism appears to be similar between primates and rats following a
saturating dose of MeOH (Tephly et al., 1964; Makar et al., 1968; Kavet
and Nauss, 1990). This is in contrast to mice, in which the reported rate
of MeOH metabolism is approximately twice as fast as that in both
primates and rats (Mannering et al., 1969) (Table 7.2).
7.1.5.2 Dose of Methanol and Route of Exposure Following an
8-hour inhalation exposure of 5000 ppm MeOH, the blood MeOH
concentration and daily dose have been determined for mice and rodents
and projected for humans, where mice exhibit a 17-fold higher calcu-
lated plasma concentration than humans (Perkins et al., 1995). Different
routes of MeOH exposure in various animal models and humans via i.p.
injection, oral ingestion, and inhalation may produce different peak
plasma concentrations of MeOH, not to mention its metabolites, in both
the mother and developing embryo, which may alter developmental
risks.
7.2 SPECIES DIFFERENCES IN METHANOL METABOLISM
7.2.1 Enzymes and Pathways
Additional comments on species differences particularly in comparison
to humans are provided in Section 7.1.5.1.
7.2.1.1 Alcohol Dehydrogenase (ADH1) ADH1 (EC 1.1.1.1) is an
oxidoreductase enzyme responsible for the metabolism of alcohols into
their corresponding aldehydes, using nicotinamide adenine dinucleotide
(NAD
รพ
) as a cofactor (Lutwak-Mann, 1938) (Figure 7.2). The enzyme is
constructed of two subunits, each subunit being one of six possible
subunits (
a
,
b
,
g
,
p
,
x
,or
s
), where the class 1 isoenzymes of ADH1 are
of the
variety (Kedishvili et al., 1995). ADH1 is highly
expressed in the liver, and each isoenzyme has a varying capacity to
metabolize alcohols (Wagner et al., 1983).
aa
,
ab
,or
ag
