Folic Acid

What Is It?

Folate and folic acid are often used interchangeably as they elicit biologically equivalent effects in the body. Within the literature, folate refers to the naturally occurring form of vitamin B9 while folic acid denotes the synthetic form of vitamin B9 used in fortified food products$^{1}$. As the primary aim of this article is to offer a comprehensive overview of the effects of these compounds, both ‘folate’ and ‘folic acid’ will refer to the same compound. Folate is a water-soluble vitamin that is naturally found in legumes and dark green vegetables$^{1}$. Upon ingestion, this vitamin undergoes a multistep enzymatic transformation to form the active ingredient, 5-methyltetrahydrofolate (5-MTHF) that is subsequently absorbed into the blood$^{1}$. Unlike folate, folic acid is converted into 5-MTHF in the liver. However, both compounds eventually transform into the same active ingredient which thus underscores their biological equivalence. This vitamin is an essential component of our diets, especially for expectant mothers as it plays a role in preventing neural tube defects in developing fetuses$^{2}$. In cancer, the role of folate is complex and contentious, with evidence suggesting potential cancer-preventing benefits in some contexts, yet possible cancer-promoting effects in others, highlighting the need for more research to unravel these intricacies.

What Are Its Other Names?

Folate is commonly referred to as vitamin B9 or folacin$^{3}$. The IUPAC name for both folate and folic acid is (2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid$^{4}$. In clinical practice, folate may also be referred to as leucovorin, a prescription drug for chemotherapy$^{5}$. However, this article will predominantly focus on the dietary intake of folate and folic acid, and will thus exclude any discussions pertaining to leucovorin and folate-related drugs$^{5}$.

What Foods Have It?

Folate is naturally found in an array of vegetables and legumes, and folate content is highest among edamame and lentils. The following table illustrates different types of produce and their respective folate content$^{6}$.

It is essential to note that the content of folate is presented as an average, as the amount of folate can vary significantly depending on a variety of factors.

What Are Its Main Benefits?

Benefits for Cancer Prevention Folate has attracted the interest of the scientific community for its potential to prevent a variety of cancer types. Of the different cancer types, the relationship between folate intake and colorectal cancer risk has been studied most extensively, and will thus be the focus of this section. In one study involving 37,916 middle-aged women, it was reported that a higher dietary intake of folate was correlated with a reduced risk of colorectal cancer$^{7}$.  Correspondingly, several other observational studies have also highlighted a similar protective effect associated with folate consumption in the development of colorectal cancer$^{8-11}$.   Several randomized controlled trials investigating folate status and colorectal cancer have also supported an inverse relationship between folate consumption and colorectal cancer incidence. For instance, in one study involving 204 participants, folate consumption was shown to elicit a potentially beneficial effect on putative biomarkers of colorectal cancer risk, namely DNA methylation and DNA damage$^{12}$. In a separate study, folate intake was reported to inhibit the initial development of colorectal tumours$^{13}$. Evidently, both the randomized controlled trials and observational studies consistently demonstrate an inverse association between folate status and colorectal cancer risk. Beyond colorectal cancer, folate consumption has demonstrated cancer-fighting properties against gastric cancer. In two separate studies, folate was shown to improve precancerous gastric lesions$^{14,15}$.  Gastric lesions are characterised as abnormalities in the stomach lining which may predispose an individual to gastric cancer. These include gastric hyperplasia, erosion, or ulceration$^{16}$. Therefore, folate’s ability to eliminate these premalignant lesions is beneficial to help suppress gastric cancer in its early stages. Additionally, folate consumption is associated with a decreased risk of other types of cancer, such as breast, cervical, and lung cancer$^{17-19}$.  However, these results were not always consistent as similar studies have shown no association between folate intake and cancer risk. Therefore, the relationship between folate status and these cancer types remains an active area of research. Benefits for Cancer Recurrence Prevention Folic acid supplementation is also associated with decreased recurrence of colorectal adenomas. Colorectal adenomas are defined as benign tumours that form in the lining of the colon with the potential to develop into colorectal cancer, consequently warranting the need for early diagnosis and treatment$^{20}$. In one study, it was shown that folic acid supplementation resulted in the reduction of colorectal adenoma recurrence$^{21}$. However, studies exploring this association are relatively limited, and further investigation is therefore required to adequately describe this relationship. Benefits for Side Effects of Methotrexate Therapy Methotrexate is a chemotherapy drug that can also be administered for the treatment of autoimmune diseases such as rheumatoid arthritis. In the context of cancer, methotrexate elicits its effect by inhibiting the conversion of dihydrofolate into tetrahydrofolate, thus reducing the levels of the active form of folic acid used for the synthesis of DNA and RNA, consequently blocking cancer cell division$^{22}$. Meanwhile, in autoimmune diseases, methotrexate suppresses the metabolism of nucleotides to enhance their anti-inflammatory effect$^{22}$. However, despite the drug’s evident benefits, the use of methotrexate is also accompanied by several side effects, such as diarrhea, stomach pain and loss of appetite$^{22}$. Studies have shown that folate supplementation can help dampen the gastrointestinal intolerance associated with methotrexate treatment$^{22-24}$.  However, it is important to note that concurrent administration of folate and methotrexate may interfere with cancer treatment regimens because methotrexate exerts its cancer-fighting properties by depleting tetrahydrofolate stores in the body. Therefore, administering folate may be counterproductive in this context. This consequently underscores the importance of consulting with a physician before beginning any supplements during your cancer treatment plan. Benefits for Neural Tube Defects Prevention Perhaps the most widely discussed benefit of folate consumption is its ability to prevent neural tube defects in developing fetuses, and therefore folate consumption has grown to be synonymous with supporting fetal growth and development. Several clinical trials have established that folate deficiency is strongly correlated with the occurrence of neural tube defects$^{25-27}$. In fact, countries like Canada, South Africa, and Australia witnessed a decline in the incidence of neural tube defects following the mandatory fortification of bread flour with folic acid in 1990s$^{25}$. This highlights the importance of incorporating an adequate amount of folate into our diets, especially for expectant mothers. Benefits for Cardiovascular Disease Prevention Besides cancer and neural tube defects, folate intake has also been shown to reduce the risk of cardiovascular disease$^{28}$.  Folate is involved in reducing endogenous levels of homocysteine, an intermediate compound formed during the conversion of methionine to cysteine$^{28,29}$. Elevated homocysteine levels are associated with increased risk of cardiovascular disease$^{28,29}$. In one study, it was found that folic acid supplementation resulted in a statistically significant reduction in homocysteine levels which consequently hindered the development of cardiovascular disease$^{30}$.

What Are Its Main Drawbacks?

Potential Kidney Toxicity A potential drawback of folate consumption is that it may lead to acute kidney injury by inducing ferroptosis (a unique form of programmed cell death characterised by iron accumulation)$^{31}$. Several mouse models have shown that while moderate doses of folic acid offer health benefits, high doses of folic acid may be accompanied by ferroptosis in renal tubular cells and acute kidney injury$^{32,33}$. This is largely due to the abundance of folate receptors in the kidney that ensures almost total reabsorption of folate into the bloodstream, thereby causing an accumulation of folate in the kidney$^{34}$. However, it is important to note that these studies were conducted using in vivo mouse models, and may not necessarily elicit the same response when administered in humans, but a certain degree of caution should still be maintained, nonetheless. Potential Drug Interactions Folate has also displayed some potential interactions with certain classes of drugs. For instance, folate has been shown to interfere with the metabolism of anticonvulsant drugs, such as phenytoin and primidone, which are used in the treatment of epilepsy and seizures$^{2}$. Furthermore, folate is also known to disrupt the effectiveness of barbiturates (central nervous system depressants that are typically administered for conditions like seizures, anxiety and insomnia)$^{2}$. Potential to Mask Vitamin B12 Deficiency One of the main concerns surrounding folic acid supplementation is that it may mask vitamin B12 deficiencies. Both folic acid and vitamin B12 overlap in the methylation cycle. The methylation cycle generates methylation products that eventually lead to the formation of red blood cells and myelin proteins to support the nervous system$^{35}$. Therefore, when folic acid and vitamin B12 are deficient, regular blood cell production is no longer supported, resulting in a specific type of anemia known as pernicious anemia. However, high levels of folic acid can resolve the symptoms associated with anemia as it can resume the production of 5-MTHF and thus enable more red blood cells to be generated$^{35}$. However, folic acid alone will not compensate for the lack of vitamin B12 which is integral to the production of myelin protein. As a result, the production of myelin protein will be suspended,and this will consequently lead to the development of neurological symptoms$^{35}$. Potential Cancer-Promoting Effects The evidence surrounding the protective role of this micronutrient in cancer development is highly contentious as the supplementation of this micronutrient has displayed some potential in promoting cancer. It may exhibit cancer-promoting or cancer-preventing effects depending on a variety of factors, such as the timing of intervention, treatment dose, treatment duration, and whether folic acid or folate was administered$^{36-43}$. Firstly, the timing of intervention may play a crucial role in determining the exact effects of this micronutrient. Several studies have shown that while folic acid intake is beneficial during the initial stages of cancer development, once precancerous cells have been established, folic acid consumption may accelerate cancer proliferation instead$^{36-38}$. This evidence offers some insight into the possible implications of the timing of intervention, which thus underscores the importance of a more personalized approach to fighting cancer from one patient to another. In addition to the timing of the intervention, the dosage administered is also very important. It has been shown that low to moderate levels of folic acid are associated with a protective role as they are able to suppress cancer development. Meanwhile, high levels of folic acid are linked to the promotion of cancer. However, given that these higher folate doses are not achievable in a standard diet, it may be rare to encounter these harmful effects$^{38}$. Similarly, folate consumption has also been shown to promote sessile serrated adenomas/polyps (SSA/Ps)$^{39}$. SSA/Ps are growths found along the lining of the colon with a flattened appearance, which were recently identified to be cancer precursors$^{40-42}$. One trial involving 1,021 participants demonstrated that folate consumption led to an increased risk of SSA/Ps, thus underscoring the potential risk of folate in promoting colorectal cancer$^{39}$. However, the study noted that the increased risk did not persist once folic acid supplementation was stopped. This therefore prompts more investigation into the possible interactions between the treatment duration of folic acid supplementation and colorectal cancer risk. Interestingly, in one study conducted in men with a history of colorectal adenomas, folic acid demonstrated a potentially harmful effect as it was shown to elevate prostate cancer risk$^{43}$. Folate, on the other hand, was reported to have a protective effect on prostate cancer$^{43}$. This raises questions about the nature of these micronutrients and how they might influence the risk of cancer. More research is still required to explore how these seemingly identical micronutrients elicit these demonstrated antagonistic effects on the development of cancer.

What Are Its Mechanisms of Action?

1. Promotion of DNA Methylation: Aberrant DNA and RNA methylation (which includes both hyper and hypomethylation) are heavily implicated in cancer development as they are associated with an altered gene expression profile$^{44-46}$. Folate has been shown to regulate the methylation of genes involved in carcinogenesis. As discussed in ‘What Are its Main Benefits?’, folate plays an essential role in the generation of an important methyl donor for DNA and RNA methylation known as S-adenosylmethionine (SAM)$^{46}$. It has been shown that increased folate intake is linked to promoting the methylation of certain CpG islands (short DNA segments with cytosine and guanine nucleotides linked to phosphates) which consequently leads to the suppression of important oncogenes (mutated genes that are expressed in cancer cells)$^{46,47}$. This means that folate may have the potential to hinder cancer progression. In a different study, treatment with folic acid was demonstrated to increase DNA methylation, and consequently decrease the expression of two proto-oncogenes (genes that can lead to cells becoming cancerous) – oestrogen receptor alpha (ER-alpha) and secreted frizzled related protein-1 (SFRP-1)$^{48}$. Evidently, the role of folate in DNA and RNA methylation makes it a crucial player in gene regulation and cancer development.
2. Prevention of Uracil Misincorporation: Beyond regulating DNA methylation, folate also plays an important role in regulating the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)$^{46}$. When folate levels are low, the levels of dUMP will accumulate, and result in the misincorporation of uracil in the DNA$^{46}$. Consequently, this leads to double stranded breaks and genomic instability. In one in vivo study, it was reported that male rats on a folate-free diet experienced folate deficiency which is accompanied by double-stranded breaks in their DNA, thus supporting the association between folate deficiency and uracil misincorporation$^{49}$.
3. Reduction of Homocysteine Levels: High levels of homocysteine (Hcy) are normally linked to an increased risk of cardiovascular disease. However, recent studies have revealed that in addition to promoting cardiovascular diseases, high Hcy status may also be associated with increased cancer risk$^{50}$. Folate is known to mediate the conversion of homocysteine to methionine in the one-carbon metabolism pathway, thus decreasing endogenous Hcy levels. This may be beneficial towards cancer prevention, as elevated Hcy levels, otherwise known as hyperhomocytinuria, is associated with cancer development$^{50}$. In one in vitro study, it was reported that high homocysteine levels are associated with increased cellular proliferation and thus cancer development$^{50}$. When folate was administered, this effect was reversed, thus underscoring the potential cancer-fighting benefits of folate supplementation.

What Are Typical Doses and Durations?

Dosage Clinical studies investigating the effect of folate and folic acid intake on cancer prevention have employed a wide range of treatment doses. However, the mode of administration was consistent across all studies whereby folate and folic acid was administered orally. Furthermore, most studies generally provided either folate or folic acid, rather than a combination of both micronutrients. Studies that provided folate alone administered a dose of 5 mg/day, while studies that administered folic acid alone used doses ranging from 400 µg/day to 10 mg/day$^{14, 51-53}$. There were also studies that administered these micronutrients in combination with other nutrients like vitamin B12 and omega-3 fatty acids, in which case 15 mg/day folate, or 400 ug/day to 5 mg/day folic acid was administered$^{54-57}$. Additionally, there were also several studies that examined the dietary consumption of folate by directly measuring the nutritional status, in which case no treatment dose was administered$^{7,59}$. Duration These studies examining the anticancer properties of folate lasted anywhere between several days to several years, with the longest clinical trial lasting up to 16 years$^{7,59,60}$. Generally, studies investigating the dietary intake of folate typically persisted over a period of several years$^{62,63}$. There were also studies that investigated the role of folate as an adjuvant to cancer therapy, and these studies typically lasted over a period of several weeks or several cycles of treatment$^{64,65}$.

Summary of Data

A total of 21 randomized controlled trials were identified from the PubMed database that examined the anticancer effects of folic acid alone. A summary of the results for each cancer type is as follows:

📄 Detailed folic acid or folate (administered alone) human clinical trial study notes analyzed by Anticancer.ca

A total of 9 randomized controlled trials were identified from the PubMed database that examined the anticancer effects of folic acid as part of a multi-vitamin supplement. A summary of the results for each cancer type is as follows:

📄 Detailed folic acid (as part of multivitamin supplement) human clinical trial study notes analyzed by Anticancer.ca

A total of 2 randomized controlled trials were identified from the PubMed database that examined the folate from folate-rich foods as a means of fighting cancer. A summary of the results for each cancer type is as follows:

📄 Detailed folate or folic acid-rich food human clinical trial study notes analyzed by Anticancer.ca

A total of 10 randomized controlled trials were identified from the PubMed database that examined the association between natural folate intake and cancer risk. A summary of the results for each cancer type is as follows:

📄 Detailed folate dietary intake/association study notes analyzed by Anticancer.ca

A total of 3 randomized controlled trials were identified from the PubMed database that administered folic acid as an adjuvant for chemotherapy. A summary of the results for each cancer type is as follows:

📄 Detailed folic acid (as an adjuvant to chemotherapy) human clinical trial study notes analyzed by Anticancer.ca

A total of 4 randomized controlled trials were identified from the PubMed database that examined the anticancer effects of folic acid in combination with aspirin. A summary of the results for each cancer type is as follows:

📄 Detailed folic acid (administered with aspirin) human clinical trial study notes analyzed by Anticancer.ca

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• Folic Acid
• What Is It?
• What Are Its Other Names?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• What Are Its Mechanisms of Action?
• What Are Typical Doses and Durations?
• Summary of Data
• References
• About This Article
• Disclaimer