Oxidative Stress and Species Differences in the Metabolism, Developmental Toxicity, and Carcinogenic Potential of Methanol and Ethanol - The Toxicology of Methanol - page 185

FIGURE 7.7 Role of folate in the metabolism of FA. In the presence of
tetrahydrofolate (THF), formate is metabolized into 10-formyl-THF by 10-
formyl-THF-synthetase. 10-Formyl-THF is subsequently converted into CO 2
and H 2 O by 10-formyl-THF dehydrogenase.

7.2.1.5 Folate-dependent dehydrogenase Formic acid (FA) is metab-
olized to carbon dioxide and water by a folate-dependent
dehydrogenase. Using 10-formyl-tetrahydrofolate (THF) synthetase,
FA is converted into 10-formyl-THF, which in turn is converted into
carbon dioxide and water by 10-formyl-THF dehydrogenase (Black et
al., 1985) (Figure 7.7). This metabolic pathway is maintained in all
species; however, varying levels of the cofactor THF limit the efficiency
of FA oxidation (McMartin et al., 1981). Specifically, the mouse has
over fourfold higher basal THF levels than humans, effectively decreas-
ing the accumulation of FA and its associated toxicities (Sokoro et al.,
2008) (Table 7.7). In primates, the THF-dependent metabolic pathway
of FA oxidation becomes saturated with doses of MeOH exceeding
300mg/kg (Kavet and Nauss, 1990).
In addition to the enzyme-catalyzed metabolism of FA discussed
above, there are also H þ /formate co-transporters in the renal tubes,
which could potentially be present in the yolk sac and placenta and
subsequently affect species differences in the developmental suscepti-
bility to FA exposure (Hovda et al., 2007).

TABLE 7.7 Species Differences in Hepatic Levels of Tetrahydrofolate
(THF)
Model

THF, nmol/g Citation

Mouse 42 Sokoro et al. (2008)

Rat 11 Sokoro et al. (2008)

Monkey 8 Sokoro et al. (2008)

Human 7 Sokoro et al. (2008)

Micropig 2 Sokoro et al. (2008)

THF, tetrahydrofolate.