The susceptibility of various species to methanol toxicity is inversely related to the rate of tetrahydrofolate (H4olate)-dependent formate oxidation to carbon dioxide.Thus, the levels of various folate derivatives and folatedependent enzyme activities present in the livers of monkeys, which are sensitive to methanol, and rats, which are not, were compared in order to investigate the biochemical basis of this species difference. Hepatic H4folate levels in monkeys were 60% of those in rats, and formylated-H4folate derivatives were 2-fold higher in monkeys than in rats. No significant difference between monkeys and rats in the levels of total hepatic folate or 5-methyl-H4folate was observed. The activities of formylH4folate synthetase (EC 6.3.4.3) and formyl-H4folate dehydrogenase (EC 1.5.1.6) were 4-and 2-fold higher, respectively, in monkeys than in rats. There was no significant difference between monkeys and rats in methionine synthetase activity (EC 2.1.1.13). Dihydrofolate reductase activity (EC 1.5.1.3) in monkeys was 20% of that in rats. 5,10-Methylene-H4folate reductase (NADPH) activity (EC 1.1.1.171) in monkeys was 40% and 25% of that in rats when the rates of the forward and reverse reactions, respectively, were compared. Serine hydroxymethyltransferase activity (EC 2.1.2.1) was 2-fold higher in monkeys than in rats. The differences in the activities of methylene-H4folate reductase and serine hydroxymethyltransferase between monkeys and rats may have contributed to the difference in hepatic Il4folate levels. The 40% lower level of hepatic H4folate in monkeys, as compared to rats, relates well to the 50% lower maximal rate of formate oxidation in monkeys. Thus, the species difference in susceptibility to methanol may be explained by the difference in the level of hepatic H4folate.A species difference exists in the susceptibility to methanol toxicity (1-3), which appears to be related to the regulation of folate-dependent one-carbon metabolism (4-7). The syndrome of methanol poisoning in humans and monkeys is characterized by a mild central nervous system depression which is followed by a latent period, metabolic acidosis, ocular toxicity, and death (1-3). In contrast, rats and other rodents display only a mild central nervous system depression after methanol administration (1-3). This difference in response to methanol is related to elevated levels of formic acid in species susceptible to methanol poisoning (8-13). Thus, marked elevations of formate in body fluids and tissues occur in humans and monkeys receiving toxic doses of methanol (8, 9, 11-13); but in rats, no significant accumulation of formate is observed (8, 9). The species variation in formate accumulation is explained by the observation that, over a range of formate dose levels, the rate of formate oxidation to carbon dioxide in vivo in rats is at least twice that observed in monkeys (4). In both rats and monkeys, the major route of formate oxidation in vivo is through a folatedependent pathway (4, 5) (Fig. 1) (Fig. 1, reaction 1) (1...
