Volume 19 - Issue 2

Review Article Biomedical Science and Research Biomedical Science and Research CC by Creative Commons, CC-BY

Folate Metabolism. Polymorphisms of Methylentetrahydrofolate Reductase. Concurrent Factor in Pathogenic Effects

*Corresponding author: Luis E Voyer, Teaching and Research Committee. Hospital Pedro de Elizalde, Associated with the Faculty of Medicine, University of Buenos Aires, Argentina.

Received: June 20, 2023; Published: July 03, 2023

DOI: 10.34297/AJBSR.2023.19.002577


Human schistosomiasis is a parasitic infection that affects close to a quarter of a million people in 78 nations and the number of people at risk may be projected to 800 million. The disease is caused by Schistosoma parasites, which are blood flukes that infect humans through the skin when they come into contact with contaminated water. Schistosomiasis causes a range of symptoms, including abdominal pain, diarrhea, and blood in the urine. One of the less well-known effects of schistosomiasis is its impact on male reproductive features, germ cells and immune components in the testis. Despite the testicular cells are well equipped with innate and effective local defenses mechanisms against invading parasites. Various pathogens such as Schistosoma parasites, succeeded in hijacking the immune-privileged state of the testis and to evade systemic immune surveillance. Some pathogens can even remain in the testes for long periods of time, disrupting thus local immune homeostasis and affecting testicular function and male fertility. This article presents an overview of the Schistosoma parasites strategies used to jeopardize the testis immune priviledge.

Keywords: Testis, Immune Privilege, Human Schistosomiais


Vitamin B9, folate in its natural form is present in green vegetables, fruits and organ meats. Folic acid is the synthetic form widely used as a supplement to compensate low intakes of folate as happens with processed and ultra processed foods as habitual feeding. However, for normal biological actions folic acid must be converted into 5-methylenetetrahydrofolate (5-MTHF) by the enzyme Methylenetetrahydrofolate Reductase (MTHFR).

The function of folate is to act together with vitamins B12, B2 and B6 in the transfer of one carbon units, methylation processes on nucleotides, amino acids and phospholipids, processes of vital importance for cell division, synthesis of nucleic acids, amino acids and methionine from homocysteine [1]. Folic acid does not have normal biological actions if it is not converted by the enzyme MTHFR into 5-10-methylenetetrahydrofolate (5-10-MTHF) and 5-MTHF, the predominant form in the circulation. The bioavailabi lity of folic acid is greater than that of folate, which depends on its content in food and its absorption, which can be interfered with by antinutrients, such as alcohol [2,3] or tobacco [4]. Blood folate levels are 15% lower in smokers and reduced transport of folate to the fetus has been observed in pregnant women who smoked or abused alcohol during pregnancy [5,6]. Folate absorption is also decreased by inflammatory bowel diseases such as ulcerative colitis, regional enteritis, Crohn’s disease, or celiac disease [7].

Methionine Synthase (MS) produces methionine from the remethylation of homocysteine, methionine by action of the enzyme adenosyl transferase gives rise to its methyl donor form, S-Adenosylmethionine (SAM) essential for many methylation reactions, including methylation of DNA-by-DNA Methyl Transferase (DNMT) essential for its stabilization and control of gene expression, critical during cell differentiation [8,9]. The folate content, as well as other nutrients, varies according to age of the plant, time of the year, soil moisture and form of consumption; fresh preparations without prior cooking and fruits with a low degree of maturity have higher contents. All these differences have implications for the bioavailability of natural folate, while that of folic acid as a supplement is 100%, but when added to food it is reduced to approximately 85% [10].

Dietary folate is mostly reduced molecules while folic acid is fully oxidized. Natural sources of folate occur especially in avocado, orange, beetroot, asparagus, spinach, lettuce and broccoli. Folic acid should be considered as a medication to compensate for low folate intake from diets low in vegetables and abundant in processed foods. Although the majority of folic acid is converted into 5-MTHF, with excessive intake, high levels in the blood that have not been converted can be detected and numerous health problems can occur, such as leukemia, asthma, depression, even the progression of pre-existing neoplastic lesions or preneoplastic diseases [11-14].

Folate metabolism is compartmentalized in the cytoplasm, mitochondria, and nucleus with specific interdependent metabolic pathways. The entry of folate into cells is made by membrane transporters or by folate-binding proteins; 40% of cellular folate is in the mitochondria, 10% in the nucleus, and 50% in the cytoplasm. Folate catabolism is extremely slow but is accelerated by Methotrexat (MTX), which acts as an antifolic, with consequent DNA hypomethylation [15]. Inadequate availability of folate, consequence of a deficit in intake, malabsorption or alterations in methylation processes due to mutation polymorphisms with decreased activity of enzymes involved, mainly MTHFR, can cause metabolic alterations, lower concentration of 5-MTHF, decreased trans-sulfurization for glutathione synthesis with increased oxidative stress [3-18] and increased folic acid and homocysteine and DNA hypomethylation with increased risk for chromosomal abnormalities and various pathological processes [19].

The frequencies with which the MTHFR biotypes 677C>T and 1298A>C occur in the general population have been studied in many countries [20,21]. The dispersion of frequencies in population groups of seven of these countries [22-28] of biotypes CC, CT and TT for 677 are, respectively: 36.5-71.2%, 26-51.2% and 3.9- 20.9%; and in 5 of these countries [22-26] of biotypes AA, AC and CC for 1298 are: 39.8-70.1%, 8.8-47.2% and 3.6-13-5%. The determination of these biotypes is carried out by PCR [29] techniques and we have required it in certain clinical cases, but no studies have been carried out in Argentina in order to show frequency in our population.

Prevention of Recurrences

Faced with a history of disorders such as those referred, the presence of MTHFR biotypes, mainly C677C and/or T677T, and/ or A1298C and/or C1298C, can prevent recurrences by reducing the risk, with the substitution of folic acid supply, by L 5-MTHF supplied together with vitamin B12, B6, B2, C and D with controls to maintain normal levels of the same and homocysteine. 5-MTHF must necessarily be specified to be the left-handed form, L 5-MTHF. The D forms should not be used due to low bioavailability. B12 levels greater than 500pg/ml, folate greater than 10mg% and homocysteine less than 10mg% should be maintained.

In recurrent pregnancy loss with a diagnosis of thrombophilia that did not respond to heparin treatment (generally successful for acquired thrombophilia) and presence of the referred MTHFR biotypes (possible hereditary thrombophilia) in addition to heparin treatment, daily supply of 5mg of L-MTHF during 3months prior gestation and 1mg the entire course of the pregnancy together with B12, B6, B2, C and D, risk of recurrence may decrease.

Side Effects of Folic Acid

A systematic investigation of publications up to 2018 with 108 articles referring to 133 meta-analyses studies with 154 controls, shows beneficial effects of folic acid supplementation in the prevention, evolution and mortality rates in various types of cancer, neurological diseases and in pregnancy and its final product, but in addition to these benefits, adverse effects are recorded, such as increased risk of prostate cancer, allergies, asthma, and depression [11-13].

In interpreting this increased risk for adverse effects, food fortification programs with folic acid should first be taken into account, such as the one implemented in 1998 in the United States, extended to a total of 80 countries, with an estimated contribution of between 100 and 200ug per person per day. In Argentina, the addition of folic acid to wheat flour is regulated along with iron, thiamine, riboflavin and niacin, in containers labeled in this regard, excluding flour intended for the production of dietary products and for export. It should be considered that this addition should be extended to all flours, such as corn and rice to cover differences in eating habits by ethnic groups or sensitivity to gluten gliadin, mainly wheat.

For women of childbearing age, the contribution should be 400ug per day. In peri-conceptional supplementation, 1mg per day should be adequate and only when there is a history of NTD disorder, this supplementation should be 5mg per day.

Higher intakes can cause high levels of circulating unmetabolized folic acid, a reason for adverse effects, especially when there are MTHFR biotypes with decreased activity.



Conflict of Interest



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