Safety evaluation of calcium L-methylfolate

Niederberger, Katherine E.; Dahms, Irina; Broschard, Thomas H.; Boehni, R.; Moser, Rudolf

doi:10.1016/j.toxrep.2019.09.012

Cited by 16 publications

(10 citation statements)

References 38 publications

(38 reference statements)

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“…Moreover, previous studies have demonstrated the excellent safety profile for the Calcium L-5-methyltetrahydrofolic acid (L-5-MTHF-Ca). Thus, it would be interesting to assess in future studies a supplementation with L-5-MTHF-Ca as a safe alternative to 5-MTHF as a source of folate, in particular for pregnant women carrying the MTHFR(677)T variant [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

et al. 2021

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Identification of causal factors that influence fetal growth and anthropometry at birth is of great importance as they provide information about increased risk of disease throughout life. The association between maternal genetic polymorphism MTHFR(677)C>T and anthropometry at birth has been widely studied because of its key role in the one-carbon cycle. MTHFR(677) CT and TT genotypes have been associated with a greater risk of low birth weight, especially in case of deficient intake of folic acid during pregnancy. This study aimed to analyze the association between the maternal MTHFR(677)C>T genetic polymorphism and anthropometry at birth in a population with adequate folate consumption. We included 694 mother–newborn pairs from a prospective population-based birth cohort in Spain, in the Genetics, Early life enviroNmental Exposures and Infant Development in Andalusia (GENEIDA) project. Women were genotyped for MTHFR(677)C>T SNP by Q-PCR using TaqMan© probes. Relevant maternal and newborn information was obtained from structured questionnaires and medical records. Results showed that maternal MTHFR(677)C>T genotype was associated with newborn anthropometry. Genotypes CT or CT/TT showed statistically significant associations with increased or decreased risk of large-for-gestational-age (LGA) or small-for-gestational-age (SGA) based on weight and height, depending on the newborn’s sex, as well as with SGA in premature neonates. The relationships between this maternal genotype and anthropometry at birth remained despite an adequate maternal folate intake.

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Section: Discussionmentioning

confidence: 99%

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

et al. 2021

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“…5-MTHF compared to folic acid was found to increase plasma folate levels more effectively [111]. Safety studies of high-dose 5-MTHF in rats showed no adverse events [112] and dosages as high as 17 mg of 5-MTHF daily for 12 weeks have been shown to have no side effects [113]. In pregnancy, there have been reported no side effects with 1.13 mg [114] and 7.5 mg and 15 mg 5-MTHF have been used without side effects in patients with depression [115,116].…”

Section: Folate Metabolismmentioning

confidence: 93%

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review

et al. 2022

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Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.

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“…The sham-operated group received a saline injection. A recent toxicity study revealed that daily oral administration of 5-MTHF (400 mg/kg) to rats for 13 weeks did not cause toxic effects on the kidneys and liver [ 40 ]. Rats with or without folic acid injection were sacrificed at 24 h after reperfusion.…”

Section: Methodsmentioning

confidence: 99%

5-Methyltetrahydrofolate Attenuates Oxidative Stress and Improves Kidney Function in Acute Kidney Injury through Activation of Nrf2 and Antioxidant Defense

et al. 2022

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Oxidative stress is a major mediator of adverse outcomes in acute kidney injury (AKI). Deficiency of micronutrients, such as folate, is common in AKI. Our previous study reported that AKI impaired kidney reabsorption of folate and decreased plasma folate level in rats. The present study investigated the effect of 5-methyltetrahydrofolate (5-MTHF), a biologically active form of folate/folic acid, on AKI-impaired kidney function and oxidative stress. Sprague-Dawley rats developed AKI after kidney ischemia (45 min) and reperfusion (24 h). Injection of 5-MTHF (3 µg/kg body weight) improved kidney function and attenuated oxidative stress with a restoration of glutathione and a reduction of lipid peroxidation in the kidney. Injection of 5-MTHF activated transcription factor Nrf2 and increased the expression of glutathione synthesizing enzymes, superoxide dismutase-1 and heme oxygenase-1 in the kidney. Simulated ischemia-reperfusion through hypoxia-reoxygenation increased oxidative stress in proximal tubular cells. Incubation of cells with 5-MTHF alleviated cell injury and increased antioxidant enzyme expression and intracellular glutathione levels. Inhibition of Nrf2 expression through siRNA transfection abolished the effect of 5-MTHF against oxidative stress. These results suggest that low-dose folic acid can improve kidney function through activation of Nrf2 and restoration of antioxidant defence. Micronutrient supplements may improve clinical outcomes in AKI.

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Safety evaluation of calcium L-methylfolate

Abstract: HighlightsThe toxicity of calcium L-methylfolate was studied.No toxic, mutagenic, teratogenic nor embryogenic effects were observed.The NOAEL for calcium L-methylfolate was 400 mg/kg bw/day.

Cited by 16 publications

References 38 publications

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review

5-Methyltetrahydrofolate Attenuates Oxidative Stress and Improves Kidney Function in Acute Kidney Injury through Activation of Nrf2 and Antioxidant Defense

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Safety evaluation of calcium L-methylfolate

Abstract: HighlightsThe toxicity of calcium L-methylfolate was studied.No toxic, mutagenic, teratogenic nor embryogenic effects were observed.The NOAEL for calcium L-methylfolate was 400 mg/kg bw/day.

Cited by 16 publications

References 38 publications

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphism and Infant’s Anthropometry at Birth

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review

5-Methyltetrahydrofolate Attenuates Oxidative Stress and Improves Kidney Function in Acute Kidney Injury through Activation of Nrf2 and Antioxidant Defense

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Abstract: HighlightsThe toxicity of calcium L-methylfolate was studied.No toxic, mutagenic, teratogenic nor embryogenic effects were observed.The NOAEL for calcium L-methylfolate was 400 mg/kg bw/day.