Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol - The Toxicology of Methanol - page 179

FIGURE 7.2 Role of alcohol dehydrogenase (ADH1) in the metabolism of
MeOH. MeOH (CH 3 OH) is oxidized in humans and primates by ADH1 into
formaldehyde (CH 2 O) using NAD þ as a cofactor.

The physical properties of ADH1 differ considerably among species,
where the affinity of MeOH for ADH1 varies greatly (Mani et al., 1970;
Pietruszko, 1975a,b) (Table 7.3). In humans and non-human primates,
MeOH is preferentially oxidized to formaldehyde using the ADH1 b 1 b 1
isoenzyme (Mannering et al., 1969; Wagner et al., 1983; Blomstrand
and Ingemansson, 1984). Saturable elimination results from a limited
source of the ADH1 cofactor NAD þ and occurs following doses greater
than 0.1 g/kg MeOH in humans and non-human primates (Horton et al.,
1992; Rang et al., 2003). In contrast, rodent ADH1 makes a minimal
contribution to MeOH metabolism, as demonstrated in ADH1-deficient
mice (Bradford et al., 1993). The underlying mechanism responsible for
the inability of rodents to efficiently metabolize MeOH by ADH1
remains unknown; however, species differences in the ADH1 gene or
protein expression (Buhler et al., 1984) and differing isoenzymes (Algar
et al., 1983) have been implicated.
ADH1 activity using EtOH as a substrate has been well characterized
in humans and rodents; however, the use of MeOH as a substrate is less
understood, and therefore, assessment of species differences in ADH1
activity generally refers to the former substrate (Pikkarainen and Raiha,
1967; Algar et al., 1983; Harris et al., 2003). An interspecies compari-
son of ADH1 activity with EtOH demonstrates parallels between
humans and rodents in the increasing ADH1 activity throughout
gestation and postnatally, with highest levels being reached in

TABLE 7.3 Comparison of Enzyme Kinetic Parameters for Alcohol
Dehydrogenase (ADH1) with MeOH As a Substrate in Mice, Rats, and
Humans
Model V max K m Citation

Mouse 0.06mmol/min/kg bw 48.7 mM Ward et al. (1995)

Rat 0.03mmol/min/kg bw 48.7 mM Ward et al. (1995)

Human 0.6 Units/ m mol of active site 6 mM Wagner et al. (1983)

1 / 2 V max .

V max , maximum rate of enzyme reaction; K m , substrate concentration at