STUDIES ON METHANOL TOXICITY AND FORMATE METABOLISM IN ISOLATED HEPATOCYTES - ROLE OF METHIONINE IN FOLATE-DEPENDENT REACTIONS

Following the administration of methanol to monkeys, formate accumulates and produces a marked metabolic acidosis and ocular toxicity. Formate does not accumulate in the rat, a species not sensitive to methanol toxicity. When isolated rat hepatocytes were incubated with methanol, the rate of methanol oxidation to carbon dioxide was reduced compared to the rate of oxidation observed in the rat in vivo. Furthermore, there was an accumulation of formate similar to that seen in the monkey in vivo. The enzymes in isolated hepatocytes which mediate methanol oxidation to formaldehyde, formate and carbon dioxide are similar to those reported for the rat in vivo. Thus, formate is oxidized to carbon dioxide by folate-dependent reactions. The addition of methionine to hepatocyte incubations containing methanol enhanced the oxidation rate of methanol to carbon dioxide by stimulating the oxidation of formate. Thus, in isolated hepatocytes the accumulation of formate during methanol oxidation was due to the development of a methionine deficiency which produced an apparent functional folate deficiency leading to a reduction in the rate of oxidation of formate to carbon dioxide. The importance of methionine in formate oxidation to carbon dioxide is also apparent in hepatocyte preparations obtained from folate-deficient rats. In these hepatocytes. the addition of 5-formyltetrahydrofolate alone was ineffective in restoring formate oxidation, but it was effective when methionine was also added. Isolated hepatocytes may be a useful model for studying the factors involved in regulating the metabolism of methanol to carbon dioxide, since it is possible to regulate each step in the pathway of methanol oxidation to carbon dioxide. © 1979.