Methanol toxicity in the monkey: effects of nitrous oxide and methionine

Methanol poisoning in monkeys and humans is characterized by the development of formic acidemia, metabolic acidosis and ocular toxicity. Formate, the metabolite associated with the toxicity of methanol, is oxidized to carbon dioxide by a tetrahydrofolate-dependent pathway. Nitrous oxide treatment was used to inhibit the tetrahydrofolate-generating enzyme, 5-methyltetrahydrofolate homocysteine methyltransferase (methionine synthetase, E.C. 2.1.1.13.), to delineate the role of this enzyme in regulating formate oxidation in the monkey. The importance of methionine in the regulation of formate oxidation in the monkey also was evaluated. Nitrous oxide inhibited the oxidation of formate generated from the metabolism of methanol (1 g/kg i.p.) in the monkey, resulting in the development of severe metabolic acidosis and high blood formate levels in these animals compared with air-breathing monkeys administered the same dose of methanol. Treatment of nitrous oxide-exposed monkeys with repetitive doses of methionine (100 mg/kg 10, 12 and 14 hr after methanol) reversed the effects of nitrous oxide on formate oxidation, resulting in a marked decrease in blood formate levels and an increase in the rate of [14C]O2 formation from methanol. Methionine treatment also reversed the development of metabolic acidosis and bicarbonate depletion observed in nitrous oxide-exposed monkeys. These results indicate that hepatic methionine synthetase is important in the regulation of tetrahydrofolate-dependent metabolism in the monkey and that the generation of tetrahydrofolate by this enzyme is a major factor in determining the sensitivity of a species to methanol poisoning.