Methanol toxicity and formate oxidation in NEUT2 mice.
NEUT2 mice are deficient in cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH; EC 1.5.1.6) which catalyzes the oxidation of excess folate-linked one-carbon units in the form of 10-formyltetrahydrofolate to CO{sub 2} and tetrahydrofolate. The absence of FDH should impair the oxidation of formate via the folate-dependent pathway and as a consequence render homozygous NEUT2 mice more susceptible to methanol toxicity. Normal (CB6-F1) and NEUT2 heterozygous and homozygous mice had essentially identical LD50 values for methanol, 6.08, 6.00, and 6.03 g/kg, respectively. Normal mice oxidized low doses of [{sup 14}C]sodium formate (ip 5 mg/kg) to {sup 14}CO{sub 2} at approximately twice the rate of homozygous NEUT2 mice, indicating the presence of another formate-oxidizing system in addition to FDH. Treatment of mice with the catalase inhibitor, 3-aminotriazole (1 g/kg ip) had no effect on the rate of formate oxidation, indicating that at low concentrations formate was not oxidized peroxidatively by catalase. High doses of [{sup 14}C]sodium formate (ip 100 mg/kg) were oxidized to {sup 14}CO{sub 2} at identical rates in normal and NEUT2 homozygous mice. Pretreatment with 3-aminotriazole (1 g/kg ip) in this instance resulted in a 40 and 50% decrease in formate oxidation to CO2 in both normal and homozygous NEUT2 mice, respectively. These results indicate that mice are able to oxidize formate to CO{sub 2} by at least three different routes: (1) folate-dependent via FDH at low levels of formate; (2) peroxidation by catalase at high levels of formate; and (3) by an unknown route(s) which appears to function at both low and high levels of formate. The implications of these observations are discussed in terms of the current hypotheses concerning methanol and formate toxicity in rodents and primates.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE
- DOE Contract Number:
- DE-AC02-06CH11357
- OSTI ID:
- 949494
- Report Number(s):
- ANL/BIO/JA-41485; ABBIA4; TRN: US201012%%284
- Journal Information:
- Arch. Biochem. Biophys., Vol. 393, Issue 2 ; Sep. 15, 2001; ISSN 0003-9861
- Country of Publication:
- United States
- Language:
- ENGLISH
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