Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate
Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervent...
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doaj-5cb52249ef8140cca4449d82fa19a1972020-11-25T03:40:28ZengMDPI AGJournal of Clinical Medicine2077-03832020-09-0192836283610.3390/jcm9092836Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-MethyltetrahydrofolateMaša Vidmar Golja0Alenka Šmid1Nataša Karas Kuželički2Jurij Trontelj3Ksenija Geršak4Irena Mlinarič-Raščan5Research Unit, Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Šlajmerjeva 3, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaResearch Unit, Department of Obstetrics and Gynecology, University Medical Centre Ljubljana, Šlajmerjeva 3, 1000 Ljubljana, SloveniaFaculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, SloveniaAdequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (<i>n</i> = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.https://www.mdpi.com/2077-0383/9/9/28365,10-methylenetetrahydrofolate reductase (MTHFR) polymorphismsfolate supplementationfolic acid (FA)5-methyl-tetrahydrofolate (5-Me-THF) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maša Vidmar Golja Alenka Šmid Nataša Karas Kuželički Jurij Trontelj Ksenija Geršak Irena Mlinarič-Raščan |
spellingShingle |
Maša Vidmar Golja Alenka Šmid Nataša Karas Kuželički Jurij Trontelj Ksenija Geršak Irena Mlinarič-Raščan Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate Journal of Clinical Medicine 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms folate supplementation folic acid (FA) 5-methyl-tetrahydrofolate (5-Me-THF) |
author_facet |
Maša Vidmar Golja Alenka Šmid Nataša Karas Kuželički Jurij Trontelj Ksenija Geršak Irena Mlinarič-Raščan |
author_sort |
Maša Vidmar Golja |
title |
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate |
title_short |
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate |
title_full |
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate |
title_fullStr |
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate |
title_full_unstemmed |
Folate Insufficiency Due to MTHFR Deficiency Is Bypassed by 5-Methyltetrahydrofolate |
title_sort |
folate insufficiency due to mthfr deficiency is bypassed by 5-methyltetrahydrofolate |
publisher |
MDPI AG |
series |
Journal of Clinical Medicine |
issn |
2077-0383 |
publishDate |
2020-09-01 |
description |
Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (<i>n</i> = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells’ metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices. |
topic |
5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms folate supplementation folic acid (FA) 5-methyl-tetrahydrofolate (5-Me-THF) |
url |
https://www.mdpi.com/2077-0383/9/9/2836 |
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