Methanol toxicity is observed in monkeys and humans but is not seen in rats or mice. The expression of
methanol poisoning is related to the ability of an animal to metabolize
formate to
carbon dioxide. Since the rate of
formate oxidation is related to hepatic
tetrahydrofolate (H4folate) content and the activities of
folate-dependent
enzymes, studies were designed to determine hepatic concentrations of H4folate and activities of
folate-dependent
enzymes of human liver and livers of species considered insensitive to
methanol poisoning. An excellent correlation between hepatic H4folate and maximal rates of
formate oxidation has been observed. In human liver, H4folate levels were only 50% of those observed for rat liver and similar to those found in monkey liver. Total
folate was also lower (60% decreased) in human liver than that found in rat or monkey liver. Interestingly, mouse liver contains much higher hepatic H4folate and total
folate than rat or monkey liver. This is consistent with higher
formate oxidation rates in this species. A second important observation has been made.
10-Formyltetrahydrofolate dehydrogenase activity, the
enzyme catalyzing the final step of
formate oxidation to
carbon dioxide, was markedly reduced in both monkey and human liver. Thus, two mechanisms may be operative in explaining low
formate oxidation in species susceptible to
methanol toxicity, low hepatic H4folate levels and reduced hepatic
10-formyltetrahydrofolate dehydrogenase activity.