Methanol poisoning and formate oxidation in nitrous oxide-treated rats

Formic acid does not accumulate in the rat after the administration of methanol as it does in methanol-poisoned humans and monkeys. In addition, rats do not manifest the metabolic acidosis and ocular toxicity characteristic of methanol intoxication in primates. Nitrous oxide treatment was used to inhibit 5-methyltetrahydrofolate homocysteine methyltransferase (methionine synthetase, EC 4.2.99.10) in order to delineate the role of this enzyme in regulating the metabolism of formate in rats and in determining the sensitivity of this species to methanol intoxication. Nitrous oxide treatment resulted in a decrease in hepatic levels of nonmethylated tetrahydrofolate forms and an increase in 5-methyltetrahydrofolate. Rats treated with nitrous oxide exhibited a marked decrease in the rate of oxidation of formate to carbon dioxide. The rate of disappearance of formate from the blood in these animals was decreased to half the control rate. Rats treated with nitrous oxide and administered methanol accumulated formate in blood and developed metabolic acidosis. These studies support the concept of a key role of methionine synthetase in supplying the tetrahydrofolate required for the folate-dependent oxidation of formate to carbon dioxide as well as the importance of this pathway in determining the sensitivity of a species to methanol poisoning.