Bioactive Folic Acid – Why?
Why is taking biologically active folic acid as opposed to biologically inactive folic acid so important?
The folic acid absorbed through food may be partially destroyed by cooking and industrial processes [1].
To compensate for a deficiency, biologically active folic acid should be used when possible. Synthetic folic acid must first be converted in the body in several steps into the active form. For the body, this is associated with energy expenditure and requires a series of enzymatic reactions.
Is 5-MTHF a better alternative than folic acid for the prevention of neural tube defects in pregnancy?
A study on pregnant women showed that the ability to make folic acid bioactive in vivo (that is in the body) varies greatly. People with genetic enzyme variations in the folate metabolism are rather benefiting of bioactive folic acid than folic acid. Even higher dosages of 5-MTHF (bioactive folic acid) are in contrast to folic acid well tolerable. Researchers came to the conclusion that 5-MTHF is a better alternative than conventional folic acid. In women examined in early pregnancy, the folic acid levels in the blood could be effectively raised through active folic acid [2].
Enzyme deficiencies may, despite folic acid intake (none-bioactive form), cause folic acid deficiency, and occur more frequently than expected.
For the efficient conversion various functional enzymes are necessary. Studies have shown that 40% of US Americans of Hispano American origin and 30-38% of the white population have a genetic defect of the 5-MTHF reductase. In Germany these genetic defects are at approximately 25%, and in Italy they amount to approximately 44% [3].
People who have inherited the genetic modification of both parents (homozygous) carry a significantly higher risk of cardiovascular diseases when the folic acid levels are low. Under normal circumstances, the 5-MTHF reductase activates an important intermediate product of folic acid (5.10 methylenetetrahydrofolate) into 5-methyltetrahydrofolic acid (5-MTHF). Substitution of active folic acid can compensate for genetic defects by bypassing the enzyme 5-MTHF reductase.
5-MTHF — Important for Healthy Blood Vessels and Balance of Neurotransmitters
Active folic acid (5-MTHF) is a methyl group supplier assisting in the conversion of homocysteine into methionine. Bioactive folic acid is essential for the catabolism of the cell and vessel-damaging homocysteine. In patients with coronary heart disease, the ingestion of activated folic acid (5-MTHF) resulted in a 700% higher plasma concentration than conventional folic acid does. These results were independent of a genetic mutation of the enzyme MTHF-R (methylenetetrahydrofolate reductase), which catalyzes the formation of the biologically active folate.
5-MTHF Crosses the Blood-Brain Barrier
Clinical tests show that 5-MTHF is highly bioavailable, and that it is able to cross the blood-brain barrier [4].
5-MTHF Increases BH4 (Tetrahydrobiopterin) Level
Brain penetration is very important, as the formation of tetrahydrobiopterin (BH4) is stimulated in the brain. In the brain, BH4 is essential for the formation of the neurotransmitter serotonin, and L-dopa (from tyrosine). L-Dopa is changed into dopamine. L-dopa is a precursor of the neurotransmitters adrenaline and noradrenaline.
Bioactive Folic Acid Lowers Homocysteine Levels Better than Folic Acid
Biologically active folic acid effectively promotes the degradation (catabolism) of the cell and vessel- damaging homocysteine into its harmless components. 5-MTHF lowers unlike “conventional” folate (folic acid homocysteine levels better (more effectively). A study on liver transplant patients showed significantly greater reductions in homocysteine levels by bioactive folate than conventional folate [5].
Vascular Damage Caused by Homocysteine
The endothelial cells of the vascular endothelium can be damaged by too high homocysteine levels. In this process, reactive oxygen species (ROS) and thus the resulting oxidative stress play a crucial role. This may contribute to the development of arteriosclerosis [6] [7].
HThe main constituents of arteriosclerotic plaques are large lipid-laden foam cells. These occur when macrophages die after excessive intake (disposal) of oxidized LDL cholesterol.
Homocysteine causes a change in the endothelial cell surface. Via an interaction of homocysteine with metal ions (e.g. iron), hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) may form [8] [9].
In lipid peroxidation, the fats of the cell membrane (cell envelope) are attacked by free radicals. Reactive oxygen species (ROS) such as H2O2 can take up electrons of lipids (fats) and thus lead to the destruction of the cell envelope. This also occurs under natural conditions.
This becomes an issue when by antioxidant mechanisms the cell is no longer able to mitigate the flood of emerging radicals and protect the cell membrane.
An intact cell membrane is essential for a healthy functioning of the cells. The lipid peroxidation of LDL cholesterol may, by formation of foam cells and proliferation of smooth muscle cells, contribute to the development of arteriosclerosis. Arteriosclerosis may lead to heart attack and stroke. In addition, the lipid peroxidation of LDL cholesterol leads to mRNA destabilization of the enzyme NO synthase in the endothelium (eNOS). This means that the conversion of the genetic information of eNOS into the finished product (enzyme) is blocked by oxidized LDL cholesterol. eNOS is an enzyme which produces NO in the vascular wall , thus regulating the vascular tone (tension) or blood pressure (see below)
[10].
High homocysteine levels promote inflammation in the body and act on the glutamate receptor (NMDA receptor).
Elevated homocysteine levels activate an inflammatory cascade in the body and also have a glutamate similar effect (NMDA receptor-mediated) not only in the nervous system, but also in the heart.
Cardiac arrhythmias and myocardial insufficiency are promoted by elevated homocysteine levels.
Homocysteine may promote cell apoptosis (e.g. of cardiomyocytes). A successive dying of heart muscle cells may lead to heart failure (cardiac insufficiency). Cardiac arrhythmias are also promoted by elevated homocysteine levels [11] [12] [13].
5-MTHF (5-methyltetrahydrofolic acid) is indispensable as a cofactor for the so-called remethylation pathway where homocysteine is degraded into methionine.
In a further step, methionine is converted into SAM (S-adenosylmethionine). SAM is essential as a methyl group supplier for various metabolic reactions in the body.
5-MTHF Helps Relieve Depression
A 5-MTHF deficiency leads to a decrease in SAM and neurotransmitter levels in the cerebrospinal fluid and promotes depression [14].
Substitution of 5-MTHF may possibly also be used for the treatment of severe depression [15].
5-MTHF Improves the Function of the Vascular Endothelium [16].
Active folic acid enhances the formation of the important cofactor BH4 (tetrahydrobiopterin) also in the vascular endothelium. An optimal ratio of BH4 to BH2 is crucial in blood vessels. Here the enzyme NO synthase (eNOS) is strongly dependent on BH4 and arginine in order to form the vascular relaxing nitric oxide (NO). A reduction of BH4 in favor of BH2 is not only counterproductive in the vessel, but also in the formation of neurotransmitters (serotonin, L-dopa). BH4 is also required for the degradation of phenylalanine into tyrosine. Tyrosine is a starting material of the important neurotransmitters dopamine, epinephrine and norepinephrine. 5-MTHF is able to prevent blood vessel damage and imbalances in the neurotransmitter household. In a human study with 117 patients, bioactive folic acid significantly improved endothelial function. The pathological decoupled enzyme eNOS was transferred back to its “normal” state by active folic acid.
5-MTHF and Nitrosative Stress
Active folate intercepts the highly toxic peroxynitrite. It is a so-called peroxynitrite scavenger (catcher) and thus preventing nitrosative stress. The dangerous peroxynitrite is formed in the final analysis, when the NO synthase decouples (uncoupling of NO synthase) and superoxide forms instead of NO (nitric oxide). For the vessels, this can have fatal consequences leading to endothelial dysfunction.
Peroxynitrite furthermore oxidized the important BH4 (tetrahydrobiopterin) and degrades the BH4 / BH2 ratio in favor of BH2.
Exactly this effect is reversed by 5-MTHF [17].
Nonbioactive Folate “Overburdens” the Folate-Forming Enzyme DHFR (Dihydrofolate Reductase)
Researchers found that, besides the MTHF reductase (see above) another essential enzyme needed for folate formation, the dihydrofolate reductase (DHFR), is extremely slow working. A high dosage of conventional folic acid (more than 1 g daily) rather leads to increased levels of the biologically inactive form, rather than the biologically active form which actually should be desired. A kind of blockage occurs because the enzyme is overburdened or saturated [18] [19].
This increased incidence of biologically inactive folic acid is seen critically among scientists.
There is even some evidence that inacitive folic acid rather inflicts damage instead of achieving the desired effects.
If non-bioactive folic acid is taken, it must be activated via the enzymes DHF-R and R-MTHF. But if a higher dosage than 200 micrograms (oral administration) is consumed, then the total folic acid cannot be bioactivated. It results in an increased incidence of unmetabolized folic acid in blood plasma [2].
Decreased Immune Function through Biologically Inactive Folic Acid from a Dosage of 230 Micrograms
Unmetabolized folic acid leads to a smaller number of NK cells and reduced immune function in animals [20].
In postmenopausal women, high dosages of non-bioactive folic acid (400 micrograms) also led to reduced resistance of NK cells. Lower dosages (below 233 micrograms) did not show this effect [21].
Gene Mutations of the Folate-Forming Enzyme (MTHFR) Increase the Risk of Cancer
Various studies indicate that mutations of the folic acid-forming enzyme methyltetrahydrofolate reductase (MTHFR) increase the risk of cancer. In an overview study, it was shown that patients with high alcohol consumption, who had inherited the defective gene from both parents (homozygous) had the highest deficiency of bioactive folic acid and simultaneously the highest risk of developing colorectal cancer [22].
Here, the administration of active folic acid might compensate for genetic defects by bypassing the enzyme 5-MTHF as opposed to biologically inactive folic acid. Therefore, an increased cancer risk could be counteracted.
Folic Acid and Vitamin B12 Deficiency Often Occur in Inflammatory Mucosal Changes of the Gastrointestinal Tract (CIBD)
In many people with folic acid and vitamin B12 deficiency inflammatory mucosal changes of the gastrointestinal tract occur [23].
Precisely an intact mucosa of the gastrointestinal tract and also a healthy liver function are basic conditions for an effective biotransformation of folic acid into active folic acid [24].
Although there are no studies up-to date on this, this would be an argument for a sublingual form of 5-MTHF.
Circulus Vitiosus (Vicious Circle):
Biologically inactive folic acid inhibits the folic acid-forming enzyme MTHF-R and leads to damage of hepatic cells and disorders of lipid metabolism.
In animals, a high consumption of non-bioactive folic acid actually resulted in inhibition of activity and quantity of the folic acid-forming enzyme methyltetrahydrofolate reductase (MTHF-R). Ultimately, the deficiency of active folic acid leads to damage of hepatic cells and disturbances in lipid metabolism.
Since the biotransformation of inactive to biologically active folic acid precisely depends on the intact functioning of hepatic cells, the effect of the biologically inactive folic acid is counterproductive [25].
Based on these findings, it is more than clear that taking bioactive folic acid is far superior to the conventional folic acid. It would be highly desirable, if a concrete implementation in clinical practice would result from these studies.
[1] Effect of different cooking methods on obtaining folic acid in folate-rich food products
[2] Active folic acid in pregnancy
[3] Gene variants of MTHF reductase and congenital anomalies
[4] Pharmacokinetic study on the use of 5-MTHF and folic acid in patients with coronary heart disease.
[5] Folic acid metabolite 5-MTHF effectively reduces serum homocysteine levels in liver transplant patients: A double-blind-placebo-controlled study
[6] Oxidative stress and inflammation of vessels in hyperhomocysteinemia
[7] Role of oxidized lipids in arteriosclerosis
[8] Endothelial cell injury by homocysteine through copper catalyzed hydrogen peroxide (H2O2)
[9] Homocysteine induces iron-catalyzed lipid peroxidation of LDL.
[10] Transcriptional and post-transcriptional regulation of endothelial NO synthase expression
[11] Activation of the mitochondrial matrix – Metalloproteinase reduces myocyte contractility with hyperhomocysteinemia
[12] Mitochondrial MMP activation, dysfunction and development of arrhythmias in homocysteinemia
[13] Hyperhomocysteinemia and sudden cardiac death: Potential mechanisms that promote cardiac arrhythmia
[14] Correlation between folic acid and depression
[15] Various forms of folic acid in depression
[16] 5-MTHF, the active form of folic acid restores the endothelial function in familial hypercholesterolemia
[17] 5-MTHF rapidly improves endothelial function and lowers the superoxide production in human vessels: effects on vascular tetrahydrobiopterin bioavailability in human vessels and on endothelial NO synthase coupling
[18] The extremely slow and fluctuating activity of dihydrofolate reductase in the human liver and consequent effects of high-dosage folic acid therapy
[19] Properties of dihydrofolate (DHF-R) from human placenta
[20] Reduced toxicity of natural killer cells through folate diet in animals
[21] Unmetabolized folic acid in plasma is associated with reduced function of natural killer cells in postmenopausal women
[22] Polymorphism in genes of the folate metabolism and colon cancer
[23] Serum folate and vitamin B12 status in patients with inflammatory bowel disease
[24] Folic acid metabolism in humans
[25] High-dose folic acid consumption leads to pseudo-MTHF-R deficiency, changes in lipid metabolism and liver damage in animals