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Methanol toxicity and formate oxidation in NEUT2 mice
R J Cook1, K M Champion, C S Giometti
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. cookrj@ctrvax.vanderbilt.edu
Archives of Biochemistry and Biophysics
|September 15, 2001
Summary
Mice lacking cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH) show normal methanol toxicity but reduced formate oxidation at low doses. This indicates alternative formate oxidation pathways exist, including a catalase-dependent route at high formate levels.
Area of Science:
- Biochemistry
- Toxicology
- Metabolic pathways
Background:
- Cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH) is crucial for oxidizing folate-linked one-carbon units.
- Mice deficient in FDH (NEUT2) were hypothesized to be more susceptible to methanol toxicity due to impaired formate oxidation.
Purpose of the Study:
- To investigate the role of FDH in formate oxidation and methanol toxicity in mice.
- To identify alternative pathways for formate oxidation in vivo.
Main Methods:
- Comparison of methanol LD(50) values in normal, heterozygous, and homozygous NEUT2 mice.
- Measurement of [(14)C]sodium formate oxidation to (14)CO(2) in vivo.
- Assessment of formate oxidation rates with and without 3-aminotriazole (catalase inhibitor) at varying formate doses.
Main Results:
- Methanol LD(50) values were similar across all mouse groups, indicating FDH deficiency does not increase methanol susceptibility.
- Homozygous NEUT2 mice exhibited approximately half the rate of low-dose formate oxidation compared to normal mice, suggesting an alternative pathway.
- High-dose formate oxidation was similar in normal and NEUT2 mice, with both showing decreased oxidation upon catalase inhibition, indicating a catalase-dependent route.
Conclusions:
- Mice possess at least three distinct formate oxidation routes: folate-dependent (FDH) at low doses, catalase-dependent at high doses, and an unknown pathway active at all doses.
- FDH deficiency does not significantly impact methanol toxicity in mice.
- The findings elucidate complex formate metabolism and its implications for understanding methanol and formate toxicity.
