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

Hanzlik, Robert P.; Fowler, Stephen C.; Eells, Janis T.

doi:10.1124/dmd.104.001289

Cited by 40 publications

(42 citation statements)

References 29 publications

(39 reference statements)

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“…To prove the link between AICAR and formyl unit availability, we fed cells 1 mM formate, which is present in human serum at 20-30 μM (Hanzlik et al, 2005;Lamarre et al, 2014). Although addition did not rescue the modest growth defects of the SHMT2 and ALDH1L2 knockout cells (Figure 1c), it fully reversed the AICAR elevation in each of the mitochondrial folate pathway deletion lines (Figure 1g), but not in the MTHFD1 hypomorphic line ( Figure S1l).…”

Section: Mitochondrial Folate Pathway Knockout Depletes 10-formyl-thfmentioning

confidence: 99%

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Ducker¹,

Chen²,

Morscher³

et al. 2016

Cell Metabolism

120

234

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SummaryOne-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. CRISPR-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-THF, and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis with the mitochondrial pathway required in nutrient poor conditions. eTOC blurbUsing genetic and metabolomic approaches, Ducker et al. dissect the roles of cytosolic and mitochondrial folate metabolism in cell proliferation, revealing that most cells default to mitochondria for making 1C units, simultaneously generating glycine, NADH and NADPH. Upon loss of the mitochondrial pathway, however, cytosolic metabolism supports tumor growth.

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Section: Mitochondrial Folate Pathway Knockout Depletes 10-formyl-thfmentioning

confidence: 99%

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Ducker¹,

Chen²,

Morscher³

et al. 2016

Cell Metabolism

120

234

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“…The residual unmetabolised formic acid and other minor metabolites are excreted via urine, faeces or expired air (Hanzlik et al, 2005).…”

Section: Safety For the Consumermentioning

confidence: 99%

Scientific Opinion on the safety and efficacy of formic acid when used as a technological additive for all animal species

2014

EFSA Journal

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This opinion concerns the re-authorisation of formic acid for use as a preservative in feed and water for drinking and as a silage additive in feed for all animal species and categories. No adverse effects are to be anticipated when formic acid is used at the maximum proposed dose in feed for pigs (12 000 mg formic acid/kg complete feed), poultry or ruminants (10 000 mg formic acid/kg complete feed). A margin of safety could not be identified. These conclusions are extrapolated to other animal species at a maximum dose of 10 000 mg formic acid/kg complete feed. Considering that the turnover of formic acid is rapid, with no evidence of accumulation in body tissues, its use in animal nutrition is not expected to contribute to consumer exposure. Therefore, the use of formic acid as a feed additive in all animal species is considered safe for the consumer. Formic acid at concentrations greater than 10 % is considered to be corrosive to skin and eyes. The acid is volatile, and exposure via inhalation for those handling the additive, as well as exposure to skin and eyes, is considered to present a risk to unprotected workers. The FEEDAP Panel considers that the use of formic acid in animal nutrition is safe for the environment. Formic acid at the recommended concentrations inhibits bacterial growth in feedingstuffs and water for drinking, and is recognised as an efficacious silage additive.

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“…10-HCO-H 4 folate synthetase forms this substrate from tetrahydrofolate (H 4 folate), formate and ATP [2]. Under normal conditions, human plasma formate concentrations range 20 -250 μM, which is about 50% of those in erythrocytes, and formate is derived from many sources [3,4]. In animals, 14 C-labeled formate given in vivo is predominantly found at C 2 and C 8 of purines, whereas only a small amount appears in the other positions [5][6][7][8][9][10], and the 14 C 2 / 14 C 8 ratio was reported to be about 1.0 [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

2007

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The 10-formyl moiety of 10-formyltetrahydrofolate is the source of carbons at the positions 8 (C 8 ) and 2 (C 2 ) of the purine ring, originating from formate and a few amino acids. Uric acid is the final catabolic product of purines. In adult humans, we independently measured the 13 C enrichment of the C 2 and C 8 positions of urinary uric acid after an oral dose of [ 13 C]sodium formate and that of the C 2 and C 8 plus C 5 positions after [2-13 C]glycine. A liquid-chromatography mass-spectrometric method was used to measure the 13 C enrichment of uric acid in urine which was collected for 3 -4 days. Purine catabolism to uric acid does not alter the positions of carbons in the ring. After the formate dose, the 13 C-enrichment at C 2 was greater that at C 8 , and a circadian rhythm was observed in the enrichment at C 2 . After the glycine dose, the C 8 plus C 5 positions were enriched, whereas no significant enrichment at C 2 was found. These 13 C enrichment patterns are not consistent with previous accepted metabolism. To our knowledge, this is the first study to investigate 13 C enrichment from formate and glycine independently into the C 2 and C 8 positions of purine in the same subjects. Possible mechanisms explaining our findings are discussed. Oral [ 13 C]formate or [2-13 C]glycine dosing and urine collection can be used to study purine biosynthesis in humans.

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

Cited by 40 publications

References 29 publications

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Scientific Opinion on the safety and efficacy of formic acid when used as a technological additive for all animal species

13C enrichment of carbons 2 and 8 of purine by folate-dependent reactions after [13C]formate and [2-13C]glycine dosing in adult humans

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