It has been found that methanol poisoning in monkeys resembles that seen in humans. However, methanol toxicity is not observed in rats. The regulation of methanol metabolism to formic acid is under study was well as the role of folate biochemistry of formate to carbon dioxode in both rats and monkeys.
The specific aims for study over the next five years are: to determine the regulation of formate oxidation by the liver for a species insensitive to methanol and species sensitive to methanol poisoning; and to study the mechanism and generation of the central nervous system toxicity of formate and other methanol metabolites. It is possible to perturb the folate biochemical pathway with nitrous oxide which has been shown to inhibit the formation of tetrahydrofolate by inhibiting methionine syntehtase activity in vivo. Since formate oxidation depends on thetrahydrofolate, it has been possible to sensitize rats to methanol posioning through the accumulation of formate. Monkeys will now be studied. Reversal of methanol poisoning in monkeys by folate administration has been done with respect to metabolic acidosis prevention. Studies will be performed to determine if ocular toxicity can be prevented. The role of folates in the central nervous system toxicity of formate will be analyzed as will the role of folates in metholation reactions in the brain as altered by formate.