levoleucovorin and formic-acid

Purine nucleotide biosynthesis de novo (PNB) requires 2 folate-dependent transformylases-5'-phosphoribosyl-glycinamide (GAR) and 5'-phosphoribosyl-5-aminoimidazole-4-carboxamide (AICAR) transformylases-to introduce carbon 8 (C8) and carbon 2 (C2) into the purine ring. Both transformylases utilize 10-formyltetrahydrofolate (10-formyl-H4folate), where the formyl-carbon sources include ring-2-C of histidine, 3-C of serine, 2-C of glycine, and formate. Our findings in human studies indicate that glycine provides the carbon for GAR transformylase (exclusively C8), whereas histidine and formate are the predominant carbon sources for AICAR transformylase (C2). Contrary to the previous notion, these carbon sources may not supply a general 10-formyl-H4folate pool, which was believed to equally provide carbons to C8 and C2. To explain these phenomena, we postulate that GAR transformylase is in a complex with the trifunctional folate-metabolizing enzyme (TFM) and serine hydroxymethyltransferase to channel carbons of glycine and serine to C8. There is no evidence for channeling carbons of histidine and formate to AICAR transformylase (C2). GAR transformylase may require the TFM to furnish 10-formyl-H4folate immediately after its production from serine to protect its oxidation to 10-formyldihydrofolate (10-formyl-H2folate), whereas AICAR transformylase can utilize both 10-formyl-H2folate and 10-formyl-H4folate. Human liver may supply AICAR to AICAR transformylase in erythrocytes/erythroblasts. Incorporation of ring-2-C of histidine and formate into C2 of urinary uric acid presented a circadian rhythm with a peak in the morning, which corresponds to the maximum DNA synthesis in the bone marrow, and it may be useful in the timing of the administration of drugs that block PNB for the treatment of cancer and autoimmune disease.

Topics: Carbon; Circadian Rhythm; Folic Acid; Formates; Glycine; Humans; Leucovorin; Phosphoribosylaminoimidazolecarboxamide Formyltransferase; Phosphoribosylglycinamide Formyltransferase; Purine Nucleotides; Serine; Uric Acid

Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes.. Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells.. Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness.. For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost.. The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.

Topics: Ethanol; Fomepizole; Formates; Humans; Leucovorin; Methanol; Poisoning; Practice Guidelines as Topic; Pyrazoles; Renal Dialysis

Topics: Animals; Escherichia coli; Formate-Tetrahydrofolate Ligase; Formates; Glycine Hydroxymethyltransferase; Leucovorin; Neurospora crassa

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Dietary Supplements; Female; Formates; Humans; Leucovorin; Metabolic Networks and Pathways; Methotrexate; Mice, Inbred C57BL; Mitochondria; Vitamin B Complex

One-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. Clustered regularly interspaced short palindromic repeats (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-tetrahydrofolate (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.

Topics: Aminoimidazole Carboxamide; Carbon; Cell Compartmentation; Cell Proliferation; Colonic Neoplasms; CRISPR-Cas Systems; Cytosol; Folic Acid; Formates; Gene Knockout Techniques; Gene Library; Glycine; Glycine Hydroxymethyltransferase; HCT116 Cells; HEK293 Cells; Humans; Leucovorin; Metabolic Networks and Pathways; Methylenetetrahydrofolate Dehydrogenase (NADP); Mitochondria; Mutation; NADP; Ribonucleotides; Serine; Xenograft Model Antitumor Assays

To present a case of survival without visual and central nervous system sequelae at a formate concentration of twice the reported lethal level.. This was a case of a 33-year-old man who ingested 1 liter of a toxic mixture of methanol and ethanol. Upon admission, he presented with anxiety, tachycardia and hypertension and had a serum formate level of 1,400 mg/l (normal range 0.9-2.1 mg/l), a methanol level of 806 mg/l (normal range 2-30 mg/l), an undetectable ethanol concentration and a normal lactate level. A 10% solution of ethanol and folinic acid was administered intravenously and two 8-hour sessions of intermittent hemodialysis were performed. The patient was discharged on the fifth day without sequelae of poisoning. The follow-up examinations 3 months and 2 years later revealed no damage to the basal ganglia. The patient had normal visual-evoked potential and findings on optical coherence tomography. The genetic analysis revealed a rare minor allele for the gene coding CYP2E1 enzyme of the microsomal ethanol oxidizing system.. The patient survived acute methanol poisoning without long-term sequelae despite a high serum level of formic acid upon admission.

Topics: Adult; Ethanol; Formates; Humans; Leucovorin; Male; Methanol; Poisoning; Renal Dialysis

10-Formyltetrahydrofolate dehydrogenase is a ubiquitously expressed enzyme in the human body. It catalyses the formation of tetrahydrofolate and carbon dioxide from 10-formyltetrahydrofolate, thereby playing an important role in the human metabolism of one-carbon units. It is a two-domain protein in which the N-terminal domain hydrolyses 10-formyltetrahydrofolate into formate and tetrahydrofolate. The high-resolution crystal structure of the hydrolase domain from human 10-formyltetrahydrofolate dehydrogenase has been determined in the presence and absence of a substrate analogue. The structures reveal conformational changes of two loops upon ligand binding, while key active-site residues appear to be pre-organized for catalysis prior to substrate binding. Two water molecules in the structures mark the positions of key oxygen moieties in the catalytic reaction and reaction geometries are proposed based on the structural data.

Topics: Binding Sites; Catalysis; Crystallography, X-Ray; Formates; Humans; Leucovorin; Oxidoreductases Acting on CH-NH Group Donors; Protein Structure, Secondary; Protein Structure, Tertiary; Tetrahydrofolates

Methanol ingestion is a cause of potentially life-threatening poisoning with numerous systemic manifestations. Clinicians may overlook the possibility of acute pancreatitis in this setting. The objective of this paper is to document the incidence of this complication in a series of 22 patients and to discuss the respective role of methanol and ethanol in its pathogenesis.. A 54-year-old woman developed acute necrotizing pancreatitis following acute methanol poisoning. She was treated by hemodialysis, ethanol infusion, and folinic acid, but, despite maximal supportive therapy, she died from multiple organ failure 54 hours after the ingestion.. In a series of 22 consecutive patients admitted with a diagnosis of acute methanol poisoning, we found evidence of pancreatic damage in 11 patients. The abnormalities were present from admission and before ethanol therapy in 7 cases and developed after ethanol therapy in 4 cases. Seven patients had a history of chronic ethanol abuse, but no patient had previously suffered from acute or chronic pancreatitis. Three patients presented moderate-to-severe acute pancreatitis according to clinical and radiological criteria and required aggressive supportive therapy including peritoneal dialysis. One patient died from the direct consequences of acute necrotizing pancreatitis and 2 fully recovered from this event. Three patients evolved to brain death; autopsy revealed hemorrhagic lesions in the pancreas in only 1 case.. Clinical, biological, and radiographic signs of acute pancreatic injury may be more common than previously realized. Acute methanol poisoning appears to produce pancreatic injury, although antidotal treatment with ethanol or prior chronic ethanol abuse may be contributing factors. Because ethanol treatment may complicate the pancreatic injury, fomepizole (4-methylpyrazole) may be the preferable antidote in acute methanol poisoning.

Topics: Acute Disease; Adolescent; Adult; Aged; Alcoholism; Ethanol; Fatal Outcome; Female; Formates; Humans; Leucovorin; Male; Methanol; Middle Aged; Multiple Organ Failure; Pancreas; Pancreatitis, Acute Necrotizing; Renal Dialysis; Retrospective Studies; Risk Factors; Suicide

Topics: Acyltransferases; Amidohydrolases; Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor; Escherichia coli; Escherichia coli Proteins; Formates; Hydroxymethyl and Formyl Transferases; Leucovorin; Ligases; Phosphoribosylglycinamide Formyltransferase; Spectrophotometry; Tetrahydrofolates

Topics: Carbon Isotopes; Choline; Folic Acid; Formates; Glycine; Leucovorin; Magnetic Resonance Spectroscopy; Purines; Saccharomyces cerevisiae; Serine

Ingestion of over 60 g of formic acid by an adult is potentially fatal. We report a case of a 36-year-old woman with a history of depression who ingested 110 g of formic acid. She survived a complicated intensive care hospitalization following usage of intravenous folinic acid, urinary alkalinization, intravenous furosemide and supportive care. We suggest a management protocol aimed at minimizing formate toxicity by enhancing hepatic formate degradation via the folinic acid 'one carbon pool' and by enhanced renal elimination of formate.

Topics: Adult; Female; Formates; Furosemide; Humans; Hydrogen-Ion Concentration; Infusions, Intravenous; Kidney; Leucovorin; Poisoning; Suicide, Attempted

This paper describes studies that further explore the pharmacologic activity of the 7-hydroxy catabolite of methotrexate (7-OH-MTX). A 3-hr exposure of L1210 leukemia cells to 100 microM 7-OH-MTX produced negligible suppression of cell growth despite the build-up of intracellular polyglutamyl congeners to levels 2.7 times greater than the dihydrofolate reductase (DHFR) binding capacity. There was no evidence for direct inhibition of DHFR under these conditions based upon measurements of cellular tetrahydrofolate cofactor and dihydrofolate levels, nor was there suppression of [3H]deoxyuridine incorporation into DNA or [14C]formate incorporation into purines. When the interval of exposure to 100 microM 7-OH-MTX was increased to 6 hr, cell growth was inhibited by 60% and there was mild (approximately 50%) inhibition of purine and thymidylate biosynthesis associated with a small increase in cellular dihydrofolate and a small decline in cellular tetrahydrofolates. Consistent with weak inhibition of DHFR was the absence of significant binding of 7-OH-MTX polyglutamates to DHFR as assessed by gel filtration of cell extracts. Mild direct inhibition of purine biosynthetics by 7-OH-MTX- or MTX-polyglutamyl congeners was demonstrated based upon inhibition of [14C]formate incorporation into purines in cells pretreated with fluorodeoxyuridine so as to prevent tetrahydrofolate cofactor depletion or dihydrofolate polyglutamate build-up. Effects of a 6-hr exposure of cells to 100 microM 7-OH MTX on cell growth were reversed completely by 10 microM leucovorin; effects on cells containing comparable levels of MTX polyglutamyl congeners were unaffected by leucovorin. These studies demonstrate very weak inhibition of L1210 leukemia cell growth and purine, pyrimidine and tetrahydrofolate synthesis by the polyglutamyl congeners of 7-OH-MTX. The data suggest that effects of 7-OH-MTX polyglutamates on folate-requiring enzymes are not likely to play an important role in moderate-dose MTX regimens. However, pharmacologic activity may be expressed in high-dose MTX protocols when high blood levels of 7-OH-MTX are sustained over long intervals to the extent to which polyglutamate congeners accumulate in tumor cells and add to the much more potent inhibitory effects of MTX polyglutamates already present. Pharmacologic activity, however, would be diminished, if not completely reversed, by the concurrent administration of leucovorin.

Topics: Animals; Deoxyuridine; Folic Acid; Folic Acid Antagonists; Formates; Leucovorin; Leukemia L1210; Methotrexate; Mice; Polyglutamic Acid; Tumor Cells, Cultured

Topics: Antimetabolites; Folic Acid; Formates; Leucovorin; Streptococcus

Topics: Folic Acid; Formates; Inosine Monophosphate; Leucovorin; Nucleotides; Purines