Human Endogenous Metabolite; Microbial Metabolite; folic acid receptor; Modulation of monoaminergic systems [2]

Folic acid treatment increases the expression of BRCA1 mRNA in HepG2, Huh-7D12, Hs578T, and JURKAT cells and BRCA2 mRNA in HepG2, Hs578T, MCF7, and MDA-MB-157 cells in a dose-dependent manner. FA has no effect on any of the ovarian cell lines or the corresponding normal cells. In Hs578T cells, folic acid increases BRCA1 protein expression but not HepG2 cell expression; BRCA2 protein expression is not detected. While there are short-term effects on breast-derived cells, FA treatment has no effect on DNA repair in liver-derived cells. FA treatment has no effect on the methylation of the BRCA1 or BRCA2 DNA, however some cell lines have different levels of methylation at particular CpG loci[1].

Folic acid (50 mg/kg i.p. for 7 days) significantly reduced immobility time in mouse forced swim test (p < 0.01) and tail suspension test (p < 0.05), indicating antidepressant-like effects [2]
Folic acid supplementation (5 mg/kg diet) prevented hepatic gene expression alterations induced by low-protein diet in pregnant rat offspring [3]
Folic acid (250 mg/kg i.p.) induced acute kidney injury-to-chronic kidney disease transition in mice via mitochondrial dysfunction [6]
No folic acid (1, 5 mg/kg; interface) prevents epigenetic modifications of gene expression in chromosomal offspring in mice adapted to a new environment [3]. Folic acid (10, 50, 100 mg/kg; side) exhibits antidepressant-like effects in this behavioral mouse model [2].

Renal cell toxicity: HK-2 cells treated with folic acid (0-100 μM) for 24h. Viability assessed by MTT assay. ROS measured with DCFH-DA probe. Mitochondrial membrane potential evaluated via JC-1 staining. Protein expression analyzed by western blot [6]
All cell lines were treated with 0, 25, 50, 75, or 100 nmol/L FA for 72 hours prior to harvesting in TRI Reagent in accordance with the manufacturer's instructions in order to ascertain the impact of FA supplementation on BRCA1 and BRCA2 mRNA expression.

Animal/Disease Models: 30-40 g Swiss mice [2]
Doses: 10, 50, 100 mg/kg
Route of Administration: Oral
Experimental Results: diminished immobility time in the forced swim test (FST) (F324=11.21), and Immobility time in the tail suspension test (TST) had a significant effect (F3, 20=5.71).

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Animal/Disease Models: 30-40 g Swiss mice [2]
Doses: 1-10 nmol/site
Route of Administration: Intracerebroventricular injection
Experimental Results: diminished mouse FST (F3,22=12.31) and TST (F3,22=5.50) immobile time).

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Animal/Disease Models: Virgin female Wistar rats [3]
Doses: 1, 5 mg/kg (180 g/kg protein plus 1 mg/kg folic acid or 90 g/kg casein plus 1, 5 mg/kg folic acid)
Route of Administration: Oral administration
Experimental Results: Prevention of epigenetic modifications in liver gene expression in offspring.

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Antidepressant study: Mice received daily intraperitoneal injections of folic acid (50 mg/kg dissolved in saline) for 7 days. Behavioral tests conducted 30 min post-last dose [2]
Epigenetics study: Pregnant rats fed low-protein diet (8% casein) ± folic acid-supplemented diet (5 mg/kg diet) throughout gestation. Offspring livers analyzed at 34 days [3]
Nephrotoxicity model: Mice fasted overnight, then injected intraperitoneally with folic acid (250 mg/kg dissolved in 0.3M NaHCO₃). Kidneys harvested at multiple timepoints [6]
Oral PK study: Rats administered folic acid solution (40 mg/kg) or zein nanoparticles (equivalent dose) via oral gavage. Blood collected serially for 24h [5]

Absorption, Distribution and Excretion
Folic acid is rapidly absorbed primarily in the proximal small intestine. Naturally occurring conjugated folic acid is enzymatically reduced to folic acid in the gastrointestinal tract before absorption. After oral administration, folic acid is detectable in plasma within approximately 15 to 30 minutes; peak concentrations are typically reached within 1 hour. In a small number of healthy adults, only trace amounts of folic acid are detected in urine after a single oral dose of 100 micrograms. In one study, oral administration of 5 mg of folic acid and in another, 40 micrograms per kilogram of body weight, resulted in approximately 50% of the dose appearing in the urine. After a single oral dose of 15 mg of folic acid, up to 90% of the dose is recovered in the urine. Most metabolites appear in the urine after 6 hours; they are usually completely excreted within 24 hours. Small amounts of orally administered folic acid may also be excreted in feces. Folic acid is also present in the breast milk of lactating mothers. Tetrahydrofolate derivatives are distributed throughout the body, but are primarily stored in the liver.
After oral administration, folic acid is rapidly absorbed from the gastrointestinal tract; the vitamin is primarily absorbed in the proximal small intestine.
Folic acid in its monoglutamate form, including folic acid, is transported across the proximal small intestine via a saturated, pH-dependent process. Higher doses of pteroylmonoglutamate (including folic acid) are absorbed via an unsaturated passive diffusion process. Pteroylmonoglutamate is absorbed more efficiently than pteroylpolyglutamate.
After oral administration, peak folic acid activity in the blood occurs within 30 to 60 minutes. When synthetic folic acid is taken on an empty stomach, its bioavailability is almost 100%. The bioavailability of natural folic acid from food is approximately 50%, while the bioavailability of synthetic folic acid taken after a meal is between 85% and 100%. Approximately two-thirds of folic acid in plasma is bound to proteins. …When pharmacological doses of folic acid are taken, a significant amount of unmetabolized folic acid is detected in the plasma. The liver stores more than 50% of the body's folic acid, approximately 6 to 14 mg. The total amount of folic acid in the human body is approximately 12 to 28 mg. For more complete data on the absorption, distribution, and excretion of folic acid (11 items in total), please visit the HSDB record page.

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Metabolism/Metabolites
Folic acid is metabolized in the liver by dihydrofolate reductase (DHFR) to cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). Folic acid is converted to its metabolically active form (tetrahydrofolate) in the liver and plasma (in the presence of ascorbic acid) by dihydrofolate reductase. After absorption of 1 mg or less of folic acid, most of it is reduced and methylated in the liver to N-methyltetrahydrofolate… Folic acid is absorbed by the liver and metabolized to polyglutamate derivatives (primarily pteroylpentaglutamate), which are generated by the action of folic acid polyglutamate synthase. …Folic acid polyglutamate is released from the liver into the systemic circulation and bile. When released from the liver into circulation, the polyglutamate form is hydrolyzed by γ-glutamyl hydrolase and reverted to the monoglutamate form.

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Absorption: The bioavailability of free folic acid solution orally in rats was 43.1% ± 4.7%
Zezyme nanoparticles increased the oral bioavailability to 67.9% ± 5.4% [5]
Metabolism: In the liver, it is converted to the active metabolite: dihydrofolate → tetrahydrofolate → 5-methyltetrahydrofolate [4]
Clearance: Renal clearance: 3.7 ± 0.7 L/h [4]
Half-life: Terminal half-life: 6.3 ± 0.9 h (oral), 5.9 ± 0.8 h (intravenous) [4]

Toxicity Summary
Identification: Folic acid is an anti-anemia vitamin. Sources: Folic acid is isolated from leafy green vegetables, liver, yeast, and fruits. Synthetic folic acid is also available commercially. Folic acid is a yellow to orange-brown crystalline powder, odorless. It is readily soluble in alkalis, hydroxides, and carbonates. It is insoluble in ethanol, acetone, chloroform, and ether. The solution can be inactivated by ultraviolet light. Alkaline solutions are easily oxidized, and acidic solutions are easily heated. Indications: Used for the prevention and treatment of vitamin B deficiency. Used to treat megaloblastic and macrocytic anemia caused by folic acid deficiency. Low birth weight infants, infants breastfed by folic acid-deficient mothers, or infants with chronic diarrhea and infections may require folic acid supplementation. Other factors that may increase folic acid requirements include alcoholism, liver disease, hemolytic anemia, breastfeeding, use of oral contraceptives, and pregnancy. Folic acid has been used to reduce the risk of birth defects in fetuses born to pregnant women. Human Exposure: Major Risks and Target Organs: Folic acid toxicity is relatively low. However, adverse reactions have been reported after injectable administration. Allergic reactions to folic acid are rare. Clinical manifestations overview: Severe allergic reactions are characterized by hypotension, shock, bronchospasm, nausea, vomiting, rash, and erythema. Itching may also occur. Gastrointestinal and central nervous system adverse reactions have been reported. Apart from rare reports of allergic reactions, folic acid treatment is generally well tolerated. Bioavailability: After oral administration, folic acid is rapidly absorbed from the gastrointestinal tract. Peak serum folate levels are reached 30 to 60 minutes after oral administration. Contraindications: Use with caution in patients with impaired renal function. It is also contraindicated in patients with folic acid hypersensitivity. Folic acid should be used with caution in patients with possible folic acid-dependent tumors. Never use folic acid alone or in combination with insufficient doses of vitamin B12 to treat undiagnosed megaloblastic anemia. Although folic acid may induce a hematopoietic response in patients with megaloblastic anemia due to vitamin B12 deficiency, it does not prevent the occurrence of subacute combined spinal cord degeneration. Absorption route: Oral: After oral administration, folic acid is rapidly absorbed from the proximal gastrointestinal tract, primarily in the proximal small intestine. Naturally occurring folic acid polyglutamic acid is enzymatically hydrolyzed into monoglutamic acid in the gastrointestinal tract before absorption. After oral administration, peak folic acid activity in the blood is reached within 30 to 60 minutes. Enterohepatic circulation of folic acid has been confirmed. Distribution by exposure route: Tetrahydrofolate and its derivatives are distributed throughout all tissues of the body. The liver contains half of the body's folic acid and is the main storage site. Metabolism: After absorption, folic acid is converted to metabolically active tetrahydrofolate by hepatic dihydrofolate reductase. After absorption, folic acid is mainly reduced and methylated in the liver to N-5-methyltetrahydrofolate, which is the main transport and storage form of folic acid in the body. Larger doses of folic acid may not be metabolized by the liver and exist primarily in the blood as folic acid. Elimination by exposure route: Oral administration: In healthy adults, only trace amounts of folic acid are detected in urine after a single oral dose. After taking large doses, renal tubular reabsorption reaches its maximum, and excess folic acid is excreted unchanged in the urine. Small amounts of orally administered folic acid can be recovered in feces. Pharmacodynamics: Folic acid can be converted into various coenzymes, which mainly participate in various intracellular metabolic reactions, including the conversion of homocysteine to methionine, serine to glycine, thymidine synthesis, histidine metabolism, purine synthesis, and the utilization or generation of formic acid. In the human body, exogenous folic acid is required for nucleoprotein synthesis and the maintenance of normal erythropoiesis. Folic acid is a precursor to tetrahydrofolate, which is active and can act as a cofactor in the single-carbon transfer reaction in the biosynthesis of nucleic acids, purines, and thymidines. Adults: Currently, there is limited data on the toxicity of folic acid in humans. There have been reports of two patients experiencing exacerbated psychotic behavior during folic acid treatment. Researchers studied the cellular morphological effects of folic acid using in vitro established human oral epithelial cells. The results showed that folic acid at twice the clinical dose did not cause significant cytotoxic reactions in cultured cells. The most significant changes were the appearance of degenerative cells in the culture, characterized by edema, increased cytoplasmic transparency, cell flattening, and atypical filaments. Interactions: Folic acid treatment may increase phenytoin metabolism in folic acid-deficient patients, leading to decreased serum phenytoin concentrations. There are also reports that concomitant use of folic acid and chloramphenicol in folic acid-deficient patients may antagonize the hematopoietic response to folic acid. Concomitant use of ethoxytocin or mephenytoin with folic acid may reduce the effects of hydantoin-like drugs by increasing hydantoin metabolism. Trimethoprim acts as a folic acid antagonist by inhibiting dihydrofolate reductase; therefore, patients taking this drug must take folinic acid calcium instead of folic acid. Folic acid may also interfere with the effects of pyrimethamine. Amoxicillin (4-aminofolate) and methotrexate (4-amino-10-methylfolate) antagonize the reduction of folic acid to tetrahydrofolate. Methotrexate is still used as an antitumor drug; its activity may depend on blocking certain purine synthesis pathways (which require folic acid), thus depriving tumor cells of the compounds needed for proliferation. Calcium folinic acid is used therapeutically as a potent antidote for the toxicity of folic acid antagonists (used as antitumor drugs). Methotrexate, pyrimethamine, or triamterene can also exert folic acid antagonistic effects by inhibiting dihydrofolate reductase. Analgesics, anticonvulsants, antimalarial drugs, and corticosteroids may cause folic acid deficiency. Major adverse reactions: Rare reports of folic acid allergic reactions, including erythema, rash, pruritus, malaise, and bronchospasm. Gastrointestinal and central nervous system adverse reactions have been reported in patients taking 15 mg of folic acid daily for one month. Animal/plant studies: Mechanism of action: Folic acid toxicity is relatively low. Mouse toxicity studies have shown that folic acid can cause seizures, ataxia, and asthenia. Histopathological studies in certain strains of mice have shown that toxic doses may also cause acute tubular necrosis. Studies have shown a possible association between folic acid neurotoxicity and cholinergic receptors in the piriform cortex and amygdala.

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Interactions
Concomitant use of high doses of folic acid and pyrimethamine for the prevention of myelosuppression may antagonize the antiparasitic effects of pyrimethamine. High-dose nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, indomethacin, naproxen, mefenamic acid, piroxicam, and sulindac, may have antifolate activity. Folic acid supplementation in mice enhanced the therapeutic activity of the antifolate chemotherapy drug lometroxe and reduced its adverse effects. Daily folic acid administration enhanced the antidepressant effect of fluoxetine. For more information on interactions, please refer to the complete data on folic acid (17 items in total) on the HSDB record page. Hepatotoxicity: Normal or excessive folic acid intake does not cause liver damage or abnormal liver function. In long-term clinical trials, the incidence of elevated serum enzymes and bilirubin in the folic acid treatment group was not higher than in the placebo group. No significant side effects, elevated ALT, or hepatotoxicity were observed with high doses of folic acid (up to 15 mg daily). Effects during pregnancy and lactation: What is folic acid? Folic acid is a nutritional supplement. It is the synthetic form of vitamin folic acid (vitamin B9). Folic acid is essential for the generation and maintenance of healthy cells in the body. The body absorbs folic acid more readily than folate. Many foods contain folic acid. These foods include dark leafy green vegetables, asparagus, broccoli, avocados, beans, carrots, squash, nuts, and citrus fruits. Some foods are fortified with folic acid to enhance their nutritional value. In the United States, folic acid is added to cereals, wheat flour, corn flour, rice, and many types of bread and pasta. Many other countries also fortify wheat flour and corn flour. Taking folic acid supplements before and during pregnancy can reduce the risk of certain types of birth defects. Folic acid can be purchased as an over-the-counter supplement and is also commonly found in prenatal vitamins.
◈ How much folic acid should I take?
Generally, it is recommended to take 400 micrograms (mcg), or 0.4 milligrams (mg), of folic acid daily, regardless of whether you are pregnant. For those who are not currently taking daily folic acid supplements and are planning to become pregnant, it is recommended to start taking folic acid at least one month before conception. During pregnancy, the recommended daily intake of folic acid is 600-800 micrograms. Most people can obtain enough folic acid by eating folic acid-rich foods and taking folic acid supplements (as part of a prenatal vitamin or as a standalone supplement). In addition to the recommended daily intake of vitamins, there is a tolerable upper intake level, or "UL." The UL is the highest recommended daily intake level for most people of a nutrient. The UL for folic acid is 1000 micrograms (mcg), or 1 milligram (mg) per day. However, in some cases, it is recommended that people consume more than 1 milligram of folic acid daily before and during pregnancy. This is especially important for people with a family history of neural tube defects (spinal or cranial openings). For people taking certain medications, drinking heavily, or having intestinal disorders that prevent adequate folic acid absorption, a doctor may recommend additional folic acid supplementation. Discuss your medications and health conditions with your healthcare provider and ask if they might affect your folic acid levels. Your healthcare provider can determine the appropriate folic acid intake for you based on your specific circumstances.
◈ I am taking folic acid. Will this affect my ability to conceive?
Generally, taking folic acid does not affect pregnancy. It is recommended to supplement with folic acid daily, starting at least one month before conception.
◈ Does taking folic acid increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. Generally, taking folic acid does not increase the risk of miscarriage. Some studies suggest that folic acid may help reduce the risk of miscarriage.
◈ Does taking folic acid increase the risk of birth defects?
There is a 3-5% risk of birth defects in each pregnancy, known as the baseline risk. Taking folic acid before and during pregnancy can reduce the risk of neural tube defects (spinal or cranial openings) in the fetus. Taking folic acid may also reduce the risk of other birth defects.
◈ Does taking folic acid during pregnancy increase the risk of other pregnancy-related problems?
Taking folic acid at the recommended dosage is not expected to cause other pregnancy-related problems such as premature birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Some studies suggest that taking folic acid may reduce the risk of certain pregnancy complications, such as premature birth or gestational hypertension, and reduce the risk of stillbirth or neonatal death.
◈ Will taking folic acid during pregnancy affect a child's future behavior or learning abilities?
Currently, no studies have shown that folic acid causes behavioral or learning problems in children. Taking folic acid while breastfeeding: Folic acid is naturally present in the breast milk of well-nourished mothers. It is recommended to consume 500 micrograms (0.5 mg) of folic acid daily while breastfeeding. Infants obtain folic acid from breast milk, so adequate folic acid intake is crucial during breastfeeding. Be sure to consult your healthcare provider about all questions regarding breastfeeding.
◈ If men take folic acid, will it affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
Some studies suggest that folic acid is essential for the production of healthy sperm. In a study of infertile men, folic acid supplementation improved sperm motility (the ability of sperm to move). The recommended folic acid intake for men is 400 micrograms/day (0.4 mg/day). If you are concerned about whether you are getting enough folic acid, consult a healthcare provider. Generally, folic acid exposure from a father or sperm donor is unlikely to increase the risk of pregnancy. For more information, see the “Paternal Exposure” information sheet on the MotherToBaby website: https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Route of Exposure
Intravenous, Oral
Adverse Reactions
For the general population, a diet with daily folic acid intake below the established upper limit of 1000 micrograms has not been shown to cause any adverse health consequences. The National Toxicology Program (NTP) investigated previously considered areas of concern, including cognition (associated with vitamin B12 deficiency), cancer, diabetes and thyroid-related diseases, and hypersensitivity reactions.
Researchers identified these areas based on patient reports of previous daily intakes of more than 400 micrograms of folic acid. Overall, the NTP report concluded that there is no conclusive evidence for adverse reactions to folic acid in the areas considered. However, gastrointestinal discomfort has been reported in rare cases. This report and subsequent literature reviews emphasize the need for further research, but overall, the benefits of folic acid intake outweigh any potential risks. Furthermore, no known side effects have been identified in mandatory folic acid fortification program guidelines worldwide.

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Antidote and Emergency Treatment
Basic Treatment: Maintain an open airway. Suction if necessary. Observe for signs of respiratory failure and provide assisted ventilation if necessary. Administer oxygen via a non-invasive mask at a flow rate of 10 to 15 liters per minute. Monitor for pulmonary edema and treat as necessary… Monitor for shock and treat as necessary… Prevent seizures and treat as necessary… If eyes are contaminated, flush immediately with water. During transport, continuously flush eyes with saline… Never use emetics. If swallowed, rinse mouth and dilute with 5 ml/kg body weight to 200 ml of water, provided the patient is able to swallow, has a strong gag reflex, and does not drool… For skin burns, disinfect and cover with a dry, sterile dressing… /Class A and Class B Poisoning/

Advanced Treatment: For patients with altered mental status, severe pulmonary edema, or respiratory arrest, consider oropharyngeal or nasopharyngeal endotracheal intubation to control the airway. Positive pressure ventilation with a bag-valve-mask may be effective. Monitor heart rhythm and treat arrhythmias as needed… Initiate intravenous infusion of 5% glucose solution (SRP: maintain patency, minimum flow rate). If signs of hypovolemia appear, use lactated Ringer's solution. Watch for signs of fluid overload. Consider medical treatment for pulmonary edema… For hypotension with signs of hypovolemia, administer fluids with caution. Watch for signs of fluid overload… Use diazepam (Valium) to treat seizures… Use promecaine hydrochloride to assist eye irrigation… /Class A and Class B Poisoning/ Bronstein, AC, PL Currance; Emergency Care for Hazardous Substance Exposure. 2nd ed. St. Louis, Missouri. Mosby Lifeline. 1994, p. 10. 139

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Non-human toxicity excerpt
/Experimental animals: Acute exposure/ High doses of the drug caused nephrotoxicity in rats due to the precipitation of crystalline folic acid in the renal tubules and obstruction of urine flow.

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Protein binding
Extremely high binding rate to plasma proteins
Acute toxicity: Rat LD₅₀ > 6000 mg/kg [1]
Nephropathy: A single high dose (250 mg/kg, intraperitoneal injection) induced renal tubular necrosis and chronic fibrosis in mice [6]
Neurological effects: A dose > 15 mg/day masked vitamin B₁₂ deficiency neuropathy [1]
Drug interactions: Decreased plasma concentrations of phenytoin and phenobarbital [1]

[1]. Folic acid safety and toxicity: a brief review. Am J Clin Nutr. 1989 Aug;50(2):353-8.

[2]. Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology. 2008 Feb;54(2):464-73.

[3]. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005 Jun;135(6):1382-6.

[4]. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010 Aug;49(8):535-48.

[5]. Zein nanoparticles for oral folic acid delivery. Journal of Drug Delivery Science and Technology, 2015, 30: 450-457.

[6]. Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid. Free Radic Biol Med. 2020 Jul;154:18-32.

Therapeutic Uses
Folic acid is indicated for the prevention and treatment of folic acid deficiency, including megaloblastic anemia and nutritional anemia, as well as anemia during pregnancy, infancy, or childhood. Increased folic acid intake and/or possible folic acid supplementation are recommended in the following populations or conditions (based on a confirmed diagnosis of folic acid deficiency): alcoholism, hemolytic anemia, chronic fever, gastrectomy, chronic hemodialysis, infants (low birth weight, breastfed, or infants fed unfortified formula such as condensed milk or goat milk), intestinal diseases (celiac disease, tropical stomatitis, persistent diarrhea), malabsorption syndromes associated with hepatobiliary diseases (liver impairment, alcoholism with cirrhosis), and/or chronic stress. Pharmaceuticals (Veterinary): ...for the prevention of megaloblastic anemia, embryonic death, cervical paralysis, and periodontitis. Chicks. For more complete data on the therapeutic uses of folic acid (7 types), please visit the HSDB record page.

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Drug Warnings
Rare reports of allergic reactions to folic acid preparations, including erythema, rash, itching, malaise, and bronchospasm-induced dyspnea.
Rare reports of gastrointestinal adverse reactions, such as anorexia, nausea, bloating, flatulence, and bitter/unpleasant taste, in patients taking 15 mg of folic acid daily for one month; and central nervous system adverse reactions, such as altered sleep patterns, poor concentration, irritability, hyperactivity, excitement, depression, confusion, and impaired judgment.
Long-term use of folic acid may result in decreased serum vitamin B12 levels.
Folic acid should be used with extreme caution in patients with undiagnosed anemia, as it may mask the diagnosis. By alleviating the hematological manifestations of pernicious anemia while allowing neurological complications to progress, it can lead to serious neurological damage, potentially causing severe consequences even before diagnosis.
For more complete data on drug warnings for folic acid (7 in total), please visit the HSDB records page.

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Pharmacodynamics
Folic acid is a water-soluble B vitamin found in foods such as liver, kidneys, yeast, and leafy green vegetables. Also known as folate or vitamin B9, folic acid is an essential cofactor for enzymes involved in DNA and RNA synthesis. More specifically, the body needs folic acid to synthesize purines, pyrimidines, and methionines before they can be incorporated into DNA or proteins. Folic acid is a precursor to tetrahydrofolate, which acts as a cofactor in the formylation reactions in the biosynthesis of purines and thymidine in nucleic acids. Folic acid deficiency is thought to cause impaired thymidine synthesis, leading to defects in deoxyribonucleic acid (DNA) synthesis, which in turn leads to megaloblastic formation and megaloblastic anemia and megaloblastic anemia. Folic acid is particularly important during periods of rapid cell division, such as infancy, pregnancy, and erythropoiesis, and plays a protective role in the development and progression of cancer. Because the human body cannot synthesize folic acid endogenously, folic acid deficiency must be prevented through diet and supplements. For folic acid to function properly in the body, it must first be reduced to the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). This crucial metabolic pathway is essential for the de novo synthesis of nucleic acids and amino acids, but antimetabolite therapies (e.g., [DB00563]) disrupt this pathway because these therapies, as dihydrofolate reductase (DHFR) inhibitors, prevent DNA synthesis in rapidly dividing cells, thereby inhibiting the formation of dihydrofolate (DHF) and tetrahydrofolate (THF). Typically, serum folic acid levels below 5 ng/mL indicate folic acid deficiency, and levels below 2 ng/mL often lead to megaloblastic anemia.

C19H19N7O6

441.3975

441.14

C, 51.70; H, 4.34; N, 22.21; O, 21.75

59-30-3

70114-87-3 (Folic acid, methyl-); 134-05-4 (10-Formylfolic acid); 54931-98-5 (10-Thiofolic acid); 119770-54-6 (11-Deazahomofolic acid); 72254-43-4 (11-Oxahomofolic acid); 85597-18-8 ( 5,10-Dideazafolic acid); 111113-75-8 (5,6,7,8-Tetrahydro-8-deazahomofolic acid); 130327-67-2 ( 5-Deazaisofolic acid); 51989-25-4 ( 8-Deazafolic acid; NSC 173522); 111113-73-6 (8-Deazahomofolic acid); 14866-11-6 (Dihydrohomofolic acid); 83704-88-5 (HH-Folic acid is a derivative of vitamin B); 3566-25-4 (Homofolic acid); 11076-68-9 (Lyofolic acid); 29291-35-8 (Nitrosofolic acid; CCRIS 466); 88912-57-6 (Pyrrofolic acid); 135-16-0 (5,6,7,8-tetrahydrofolic acid; Tetrahydropteroylglutamic acid; th-folate; folate-H4); 5786-82-3 (Tetrahydrohomofolic acid); 52454-37-2 (10-Deazaaminopterin; 10-Deaza-aminopterin; NSC 311469; NSC-311469; NSC311469); 28459-40-7 (10-Formyldihydrofolate); 2800-34-2 (10-Formyltetrahydrofolic acid; 10-Formyl-THF; 10FTHF); 74163-10-3 ( 11-Thiohomoaminopterin, a close analog of 11-thiohomofolic acid); 85803-29-8 (2-Fluoroaminopterin); 5472-96-8 (3-Chloromethotrexate); 59904-24-4 (5-Methyldihydrofolate); 50998-20-4 (5-Methyltetrahydrofolate triglutamate); 73951-54-9 (6R-Leucovorin); 77739-71-0 (Acanthifolicin); 25312-31-6 (Aminoanfol, an antifolic acid compound); 31690-11-6 (Arfolitixorin free, an antifolate modulator); 149930-93-8 (Arfolitixorin sulfate); 154705-24-5 (Arfolitixorin sodium); 501332-69-0 (BGC-945); 115940-48-2 (Calcium dextrofolinate, calcium salt of a derivative of Folic Acid);26560-38-3 (Calcium methyltetrahydrofolate); 5854-11-5 (CB 3705; CB-3705; CB3705; 5,8-Dideazafolic acid); 76849-19-9 (CB 3717; CB-3717; CB3717; N(sup 10)-Propargyl-5,8-dideazafolic acid); 18921-73-8 (chlorasquin, an inhibitor of dihydrofolate reductase); 4033-27-6 (Dihydrofolate); 36093-88-6 (Dihydroaminopterin); 528-74-5 (Dichloromethotrexate); 6807-82-5 ( Diopterin, a folic acid analog); 1148151-21-6 [Folitixorin calcium, (6R)-]; 6484-89-5 (Folate sodium; Folvite sodium); 815587-59-8 [olitixorin calcium, (6S)-]; 133978-76-4 (Folitixorin sodium); 35409-55-3 (Hexaglutamate folate); 112887-62-4 (ICI 198583, an antifolate thymidylate synthase inhibitor); 31690-09-2 (Levomefolinic acid); 1423663-76-6 ( Levomefolate sodium); 1429498-11-2 ( Levomefolate magnesium); 58-05-9 ( Levoleucovorin free acid); 1492-18-8 ( Levoleucovorin calcium); 6035-45-6 ( Levoleucovorin calcium hydrate); 163254-40-8 ( Levoleucovorin sodium); 1141892-29-6 (Levoleucovorin sodium); 120408-07-3 (Lometrexol sodium); 106400-81-1 (Lometrexol free acid); 106400-18-4 (LY249543, the S-isomer of lometrexol); 136208-85-0 (LY249543, the S-isomer of lometrexol); 82339-36-4 (Lysine-iodoacetylmethotrexate, a Folic Acid Antagonist); 7413-34-5 ( Methotrexate disodium); 7532-09-4 (Methotrexate monosodium); 59-05-2 (Methotrexate free acid); 6745-93-3 (Methotrexate hydrate); 15475-56-6 (Methotrexate sodium); 66147-29-3 (Methotrexate 1-methyl ester); 67022-39-3 (Methotrexate 5-methyl este); 79573-48-1 (Mefox; (6RS)-Mefox); 2179-16-0 (Ninopterin); 41600-13-9 (NSC269401, the isotope labelled analog of Methotrexate Diglutamate; 41600-14-0 ( NSC341076 is the isotope labelled analog of Methotrexate Triglutamate); 2197232-28-1 (OSI-7904L,1843U89; racemic) 139987-54-5 (OSI-7904L,1843U89; free acid); 89-38-3 (Pteropterin); 6164-84-7 (Pteropterin monohydrate); 33611-85-7 ( Pteroylpentaglutamic acid); 112887-68-0 (Raltitrexed); 4299-28-9 (Tetrahydromethotrexate); 29701-38-0 (Triglutamate folate); 52128-35-5 (Trimetrexate)

135398658

Light yellow to yellow solid powder

1.6±0.1 g/cm3

482 °F (decomposes) (NTP, 1992)
250 °C

1.755

-1.1

6

10

9

32

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1

C1=CC(=CC=C1C(=O)N[C@@H](CCC(=O)O)C(=O)O)NCC2=CN=C3C(=N2)C(=O)NC(=N3)N

OVBPIULPVIDEAO-LBPRGKRZSA-N

InChI=1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1

(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid

FA; N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid; pteroyl-L-glutamic acid; folacin; pteroyl-L-glutamate; Folic acid; 59-30-3; Pteroylglutamic acid; Vitamin M; Folacin; PteGlu; Folacid; Folvite; Vitamin B11; Vitamin B9; Vitamin Bc; Vitamin Be; Vitamin M

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

1M NaOH: ~100 mg/mL (~226.6 mM)
DMSO: ~33.3 mg/mL (~75.5 mM)
H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 2.08 mg/mL (4.71 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)