The regulation of one-carbon oxidation in the rat by nitrous oxide and methionine

Eells, Janis T.; Black, Kurt A.; Makar, A B; Tedford, Clark E.; Tephly, Thomas R.

doi:10.1016/0003-9861(82)90162-x

Cited by 58 publications

(18 citation statements)

References 31 publications

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“…The species difference in formate accumulation is attributed to differences in hepatic tetrahydrofolate status. Hepatic tetrahydrofolate concentrations are significantly greater in rodents than in monkeys and humans (Eells et al, 1982;Black et al, 1985;Johlin et al, 1987). Furthermore, treatments which alter the levels of hepatic tetrahydrofolate modify formate metabolism and the toxic response to methanol.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, treatments which alter the levels of hepatic tetrahydrofolate modify formate metabolism and the toxic response to methanol. In rats, folate deficiency or selective reduction of tetrahydrofolate results in formic acidemia and metabolic acidosis following methanol administration, whereas no accumulation of formate or alteration in blood pH or bicarbonate is observed in control rats (Palese and Tephly, 1975;Eells et al, 1981Eells et al, , 1982Makar and Tephly, 1982;Black et al, 1985;Johlin et al, 1987). Recent studies have also demonstrated ocular toxicity in folate-deficient monkeys (Lee et al, 1994) and tetrahydrofolate-deficient rats (Eells et al, 1996(Eells et al, , 2000Seme et al, 1999).…”

Section: Resultsmentioning

confidence: 99%

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Absorption and Elimination of Formate Following Oral Administration of Calcium Formate in Female Human Subjects

Hanzlik

Fowler²,

Eells³

2004

Drug Metab Dispos

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ABSTRACT:Calcium formate is a water-soluble salt of an essential mineral nutrient with potential for use as a dietary calcium supplement. Formate ion is a product of endogenous and xenobiotic metabolism, but sustained high plasma formate concentrations (such as occur in cases of methanol poisoning) are toxic to the retina and optic nerve. Humans and primates have reduced capacity for formate oxidation compared with rodents and dogs and are thus more sensitive to methanol (and formate) intoxication. To assess the potential for accumulation of formate ion upon repeated administration of calcium formate as a potential dietary calcium supplement, we measured plasma concentrations of formate in 14 adult human subjects before and after oral administration of a single large dose of calcium formate (3900 mg; ca. 3-6 times the anticipated dose for calcium supplementation). Plasma formate concentrations increased briskly from 0.024 ؎ 0.008 mM (endogenous formate) to reach C max (0.50 ؎ 0.04 mM) at 60 min postdose and then declined with a half-life of 59 ؎ 7 min. By 225 min postdose, plasma formate concentration had returned to baseline. With such a short half-life, repeated use of calcium formate as a dietary supplement, even three times daily, should not lead to progressive accumulation of formate. These findings are discussed in light of the production of formate by endogenous and xenobiotic metabolism and the kinetics of formate during methanol poisoning.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Absorption and Elimination of Formate Following Oral Administration of Calcium Formate in Female Human Subjects

Hanzlik

Fowler²,

Eells³

2004

Drug Metab Dispos

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“…Eells et al (17) showed that the rate of formate oxidation to carbon dioxide in rats is directly related to the hepatic content of H4folate. The present report shows that hepatic H4folate concentrations in monkeys are about 60%o of the levels found in rats, which corresponds, interestingly, to the observation made by McMartin et al (4) that the maximal rate of formate oxidation in vivo in monkeys is about 50% of that in rats.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrous oxide, which reduces hepatic H4folate levels as a result of the inhibition of tetrahydropteroylglutamate methyltransferase activity (methionine synthetase; 5-methyltetrahydropteroyl-L-glutamate: L-homocysteine S-methyltransferase, EC 2.1.1.13) (Fig. 1, reaction 9) (17)(18)(19), potentiates the toxicity of methanol in monkeys (19). In rats, either folate deficiency (7) or nitrous oxide exposure (20) allows for the development of metabolic acidosis and formate accumulation in the blood after methanol administration, signs that are not observed in control rats.…”

mentioning

confidence: 99%

Role of hepatic tetrahydrofolate in the species difference in methanol toxicity.

Black¹,

Eells²,

Noker³

et al. 1985

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

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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...

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“…In a series of experiments, Eells et al (67,69,71) blocked the folate feedback loop with nitrous oxide (N20), resulting in a slowed formate oxidation and increased methanol sensitivity. The extent to which N20 slowed formate oxidation was directly related to the decrease in hepatic THF levels, demonstrating that THF concentration was the critical factor in these experiments.…”

Section: Toxicokineticsmentioning

confidence: 99%

Acute toxicity of gasoline and some additives.

Reese

Kimbrough

1993

Environ Health Perspect

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The acute toxicity of gasoline; its components benzene, toluene, and xylene; and the additives ethanol, methanol, and methyl tertiary butyl ether are reviewed. All of these chemicals are only moderately to mildly toxic at acute doses. Because of their volatility, these compounds are not extensively absorbed dermally unless the exposed skin is occluded. Absorption through the lungs and the gastrointestinal tract is quite efficient. After ingestion, the principal danger for a number of these chemicals, particularly gasoline, is aspiration pneumonia, which occurs mainly in children. It is currently not clear whether aspiration pneumonia would still be a problem if gasoline were diluted with ethanol or methanol. During the normal use of gasoline or mixtures of gasoline and the other solvents as a fuel, exposures would be much lower than the doses that have resulted in poisoning. No acute toxic health effects would occur during the normal course of using automotive fuels.

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The regulation of one-carbon oxidation in the rat by nitrous oxide and methionine

Cited by 58 publications

References 31 publications

Absorption and Elimination of Formate Following Oral Administration of Calcium Formate in Female Human Subjects

Absorption and Elimination of Formate Following Oral Administration of Calcium Formate in Female Human Subjects

Role of hepatic tetrahydrofolate in the species difference in methanol toxicity.

Acute toxicity of gasoline and some additives.

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