Methanol poisoning I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole

McMartin, Kenneth E.; Makar, A B; Martin, Guillaume; Palese, Michael; Tephly, Thomas R.

doi:10.1016/0006-2944(75)90171-4

Cited by 183 publications

(47 citation statements)

References 12 publications

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“…Of course formate is produced by the oxidation of methanol (via the combined action of alcohol dehydrogenase and acetaldehyde dehydrogenase), whether taken exogenously or arising endogenously [methanol is present in human blood at a concentration of Ϸ1 mg/l (24)]. The metabolic acidosis resulting from methanol poisoning is caused by the accumulation of formic acid (formate plus hydrogen ions) (17). Finally, formate is also produced in the endoplasmic reticulum during cholesterol synthesis (during the conversion of lanosterol to cholesterol) (28) and in peroxisomes during the ␣-oxidation of phytanic acid (39) and 2-hydroxy fatty acids (8).…”

Section: E65mentioning

confidence: 99%

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Lamarre

Molloy

Reinke

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Lamarre SG, Molloy AM, Reinke SN, Sykes BD, Brosnan ME, Brosnan JT. Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration. 1 H-NMR metabolomic analysis of sera from vitamin B12-deficient rats. In addition to the expected increases in methylmalonate and homocysteine (Hcy), we observed an approximately sevenfold increase in formate levels, from 64 M in control rats to 402 M in vitamin B 12-deficient rats. Urinary formate was also elevated. This elevation of formate could be attributed to impaired one-carbon metabolism since formate is assimilated into the one-carbon pool by incorporation into 10-formyl-THF via the enzyme 10-formyl-THF synthase. Both plasma and urinary formate were also increased in folate-deficient rats. Hcy was elevated in both the vitamin B12-and folate-deficient rats. Although plasma Hcy was also elevated, plasma formate was unaffected in vitamin B6-deficient rats (impaired transsulfuration pathway). These results were in accord with a mathematical model of folate metabolism, which predicted that reduction in methionine synthase activity would cause increased formate levels, whereas reduced cystathionine ␤-synthase activity would not. Our data indicate that formate provides a novel window into cellular folate metabolism, that elevated formate can be a useful indicator of deranged one-carbon metabolism and can be used to discriminate between the hyperhomocysteinemia caused by defects in the remethylation and transsulfuration pathways. VITAMIN B 12 DEFICIENCY RESULTS IN A WIDE SPECTRUM of hematologic and neuropsychiatric disorders. The detection of vitamin B 12 deficiency has traditionally been based on low serum vitamin B 12 levels, with supportive clinical evidence of disease. It is now recognized that serum vitamin B 12 may be insufficient to detect a deficiency, especially in the case of elderly subjects without hematologic abnormalities. The measurement of metabolites such as homocysteine (Hcy) and methylmalonic acid (MMA) has been shown to be more sensitive in diagnosing vitamin B 12 deficiency (33, 34). In a search for novel biomarkers of vitamin B 12 deficiency, we fed rats a vitamin B 12 -deficient diet and subjected their sera to 1 H-NMR metabolomic analysis. Together with the expected increased concentrations of Hcy and MMA, we found an approximately sevenfold increase in both serum and urinary formate concentrations in the vitamin B 12 -deficient animals.We confirmed that elevated formate would also be found in folate-deficient rats, since impaired folate metabolism (via the methylfolate trap) is a well-recognized consequence of vitamin B 12 deficiency (12, 31, 32) and because formate is incorporated into 10-formyl-tetrahydrofolate (THF) via 10-formyl-THF synthase (37). Both folate and vitamin B 12 deficiencies are characterized by elevated plasma Hcy. A deficiency of pyridoxal (vitamin B 6 ) also causes elevated plasma Hcy, which becomes more pronounced after methionine loading (18). This is due to impaired removal of Hcy ...

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Section: E65mentioning

confidence: 99%

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Lamarre

Molloy

Reinke

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…The five different human enzymes have broad substrate specificity, oxidizing primary and secondary alcohols and reducing their corresponding carbonyl compounds. Specific inhibitors of these dehydrogenases would be useful for defining substrate specificity, for studying the physiological roles of the enzymes and for preventing the oxidation of methanol and ethylene glycol to toxic products (2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Formamides Mimic Aldehydes and Inhibit Liver Alcohol Dehydrogenases and Ethanol Metabolism

Venkataramaiah

Plapp

2003

Journal of Biological Chemistry

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Formamides are unreactive analogues of the aldehyde substrates of alcohol dehydrogenases and are useful for structure-function studies and for specific inhibition of alcohol metabolism. They bind to the enzyme-NADH complex and are uncompetitive inhibitors against varied concentrations of alcohol. Fourteen new branched chain and chiral formamides were prepared and tested as inhibitors of purified Class I liver alcohol dehydrogenases: horse (EqADH E), human (HsADH1C*2), and mouse (MmADH1). In general, larger, substituted formamides, such as N-1-ethylheptylformamide, are better inhibitors of HsADH1C*2 and MmADH1 than of EqADH, reflecting a few differences in amino acid residues that change the sizes of the active sites. In contrast, the linear, alkyl (n-propyl and n-butyl) formamides are better inhibitors of EqADH and MmADH1 than of HsADH1C*2, probably because water disrupts van der Waals interactions. These enzymes are also inhibited strongly by sulfoxides and 4-substituted pyrazoles. The structure of EqADH complexed with NADH and (R)-N-1-methylhexylformamide was determined by x-ray crystallography at 1.6 Å resolution. The structure resembles the expected Michaelis complex with NADH and aldehyde, and shows for the first time that the reduced nicotinamide ring of NADH is puckered, as predicted for the transition state for hydride transfer. Metabolism of ethanol in mice was inhibited by several formamides. The data were fitted with kinetic simulation to a mechanism that describes the non-linear progress curves and yields estimates of the in vivo inhibition constants and the rate constants for elimination of inhibitors. Some small formamides, such as N-isopropylformamide, may be useful inhibitors in vivo.Vertebrate alcohol dehydrogenases (EC 1.1.1.1, ADH) 1 are involved in the metabolism of relatively non-polar alcohols and aldehydes (1). The five different human enzymes have broad substrate specificity, oxidizing primary and secondary alcohols and reducing their corresponding carbonyl compounds. Specific inhibitors of these dehydrogenases would be useful for defining substrate specificity, for studying the physiological roles of the enzymes and for preventing the oxidation of methanol and ethylene glycol to toxic products (2-6).Formamides and sulfoxides are analogues of the carbonyl substrates, are bound preferentially to the enzyme-NADH complex, and are potent uncompetitive inhibitors against varied concentrations of alcohol (7-15). Uncompetitive inhibitors could be especially useful for controlling alcohol metabolism since they are effective even when the concentrations of alcohol are saturating. Previous studies identified some potent uncompetitive inhibitors for human (14, 15), horse (10,11,14,15), monkey (11), and rat (10, 11) liver alcohol dehydrogenases. We now extend the studies with 14 new branched-chain and chiral formamides in order to explore active site topologies and to make more effective inhibitors for the mouse (MmADH1) and human (HsADH1C*2) enzymes. For comparison, we also studied the potency of fi...

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“…The optic nerve and other organs (brain, heart, and kidneys) with a high rate of oxygen consumption are possible targets (5). Formate accumulation is the principal, if not the only, reason for the development of acidosis, which is usually observed after methanol poisoning (6,7). Acidosis may cause the inhibition of cellular respiration and hasten the onset of cellular injury.…”

mentioning

confidence: 99%

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

Dikalova

Kadiiska

Mason

2001

Proc. Natl. Acad. Sci. U.S.A.

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Electron spin resonance spectroscopy has been used to study free radical generation in rats with acute sodium formate poisoning. The in vivo spin-trapping technique was used with ␣-(4-pyridyl-1-oxide)-N-t-butylnitrone (POBN), which reacts with free radical metabolites to form radical adducts, which were detected in the bile and urine samples from Fischer rats. The use of [ 13 C]-sodium formate and computer simulations of the spectra identified the 12-line spectrum as arising from the POBN͞carbon dioxide anion radical adduct. The identification of POBN͞ ⅐ CO 2 ؊ radical adduct provides direct electron spin resonance spectroscopy evidence for the formation of ⅐ CO 2 ؊ radicals during acute intoxication by sodium formate, suggesting a free radical metabolic pathway. To study the mechanism of free radical generation by formate, we tested several known inhibitors. Both allopurinol, an inhibitor of xanthine oxidase, and aminobenzotriazole, a cytochrome P450 inhibitor, decreased free radical formation from formate, which may imply a dependence on hydrogen peroxide. In accord with this hypothesis, the catalase inhibitor 3-aminotriazole caused a significant increase in free radical formation. The iron chelator Desferal decreased the formation of free radicals up to 2-fold. Presumably, iron plays a role in the mechanism of free radical generation by formate via the Fenton reaction. The detection of formate free radical metabolites generated in vivo and the key role of the Fenton reaction in this process may be important for understanding the pathogenesis of both formate and methanol intoxication.

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Methanol poisoning I. The role of formic acid in the development of metabolic acidosis in the monkey and the reversal by 4-methylpyrazole

Cited by 183 publications

References 12 publications

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Formate can differentiate between hyperhomocysteinemia due to impaired remethylation and impaired transsulfuration

Formamides Mimic Aldehydes and Inhibit Liver Alcohol Dehydrogenases and Ethanol Metabolism

An in vivo ESR spin-trapping study: Free radical generation in rats from formate intoxication— role of the Fenton reaction

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