Introduction
Oftentimes names can be confusing, and in the case of folic acid and folinic acid, this is rightfully so. The names sound similar, but there are major differences. Let’s review this important subject matter.
Folic acid and folinic acid are both forms of vitamin B9, which is essential for numerous biological processes, including DNA synthesis, repair, and methylation, as well as red blood cell formation. While they are closely related and often used interchangeably in certain contexts, they have distinct biochemical properties, metabolic pathways, and clinical applications. We will explore the differences between folic acid and folinic acid in terms of their chemical structure, metabolism, bioavailability, therapeutic uses, and potential side effects.
1. Chemical Structure
- Folic Acid: Folic acid is the fully oxidized synthetic form of vitamin B9. It is a monoglutamate compound, meaning it has a single glutamate moiety. Folic acid is not found naturally in foods but is commonly used in dietary supplements and fortified foods.
- Folinic Acid: Folinic acid, also known as leucovorin or 5-formyl tetrahydrofolate (5-formyl THF), is a reduced and biologically active form of folate. It is a polyglutamate derivative, meaning it has multiple glutamate residues. Folinic acid is naturally present in foods and can also be synthesized in the body from folic acid.
2. Metabolism and Bioavailability
- Folic Acid:
- Folic acid must undergo a series of enzymatic reductions to become biologically active. It is first reduced to dihydrofolate (DHF) by the enzyme dihydrofolate reductase (DHFR) and then further reduced to tetrahydrofolate (THF).
- This conversion process can be inefficient in some individuals, particularly those with genetic polymorphisms in the MTHFR gene or those taking medications that inhibit DHFR (e.g., methotrexate).
- Folic acid is highly stable and has a long shelf life, making it ideal for fortification and supplementation.
- Folinic Acid:
- Folinic acid is already in a reduced form and does not require the action of DHFR to become active. It can directly enter the folate cycle and participate in one-carbon transfer reactions.
- This makes folinic acid a more readily available form of folate, especially in individuals with impaired DHFR activity or those taking DHFR inhibitors.
- Folinic acid is less stable than folic acid and is more sensitive to heat and light.
3. Therapeutic Uses
- Folic Acid:
- Pregnancy: Folic acid is widely recommended for pregnant women to prevent neural tube defects (NTDs) in the developing fetus.
- Anemia: It is used to treat or prevent folate deficiency anemia.
- Fortification: Folic acid is added to fortified foods (e.g., cereals, bread) to address population-wide deficiencies.
- Cardiovascular Health: It is sometimes used to lower homocysteine levels, which may reduce the risk of cardiovascular disease.
- Folinic Acid:
- Methotrexate Rescue: Folinic acid is used to counteract the toxic effects of methotrexate (a DHFR inhibitor) in cancer chemotherapy or high-dose methotrexate therapy.
- Folate Deficiency in DHFR Inhibition: It is preferred over folic acid in individuals taking medications that inhibit DHFR.
- Autism and Neurological Disorders: Some studies suggest that folinic acid may benefit individuals with cerebral folate deficiency or certain neurological conditions, such as autism spectrum disorder (ASD). A recent report highlighted the benefits of folinic acid in children with autism.
https://www.cbsnews.com/news/autism-leucovorin-medicine-folic-acid/
- Cancer Therapy: Folinic acid is used in combination with 5-fluorouracil (5-FU) to enhance its anticancer effects in colorectal cancer.
4. Bioavailability and Absorption
- Folic Acid:
- Folic acid is absorbed in the jejunum (part of the small intestine) via active transport and passive diffusion. It is then converted to its active forms in the liver and other tissues.
- However, unmetabolized folic acid can accumulate in the bloodstream, particularly at high doses, which has raised concerns about potential adverse effects.
- Folinic Acid:
- Folinic acid is more readily absorbed and utilized by the body, as it bypasses the need for DHFR activity. It is particularly beneficial in individuals with impaired folate metabolism.
- It does not accumulate in the bloodstream as unmetabolized folic acid does, reducing the risk of potential toxicity.
5. Genetic Considerations
- MTHFR Polymorphisms:
- Individuals with mutations in the MTHFR gene (e.g., C677T or A1298C) have reduced ability to convert folic acid into its active forms. For these individuals, folinic acid may be a more effective supplement.
- Folinic acid bypasses the impaired enzymatic step, making it a better option for those with genetic variations affecting folate metabolism.
6. Side Effects and Safety
- Folic Acid:
- High doses of folic acid can mask vitamin B12 deficiency, potentially leading to neurological damage if left untreated.
- There is some concern that excessive folic acid intake may promote the growth of pre-existing cancers, although the evidence is inconclusive.
- Unmetabolized folic acid in the bloodstream has been associated with immune dysfunction and other health risks.
- Folinic Acid:
- Folinic acid is generally well-tolerated and has a lower risk of side effects compared to folic acid.
- It does not mask B12 deficiency and is less likely to accumulate in the bloodstream.
7. Clinical Considerations
- Folic Acid:
- Ideal for general supplementation and fortification due to its stability and low cost.
- Suitable for individuals without impaired folate metabolism.
- Folinic Acid:
- Preferred in clinical settings where rapid folate activity is needed (e.g., methotrexate rescue).
- Recommended for individuals with MTHFR mutations or those taking DHFR inhibitors.
8. Summary of Key Differences
| Aspect | Folic Acid | Folinic Acid | ||
| Chemical Form | Fully oxidized, synthetic | Reduced, biologically active | ||
| Metabolism | Requires DHFR for activation | Bypasses DHFR, directly active | ||
| Bioavailability | Lower in impaired metabolism | Higher in impaired metabolism | ||
| Therapeutic Uses | Pregnancy, anemia, fortification | Methotrexate rescue, neurological disorders, cancer therapy | ||
| Side Effects | May mask B12 deficiency, potential toxicity | Generally well-tolerated, lower risk | ||
| Genetic Suitability | Less suitable for MTHFR mutations | Suitable for MTHFR mutations |
Conclusion
Folic acid and folinic acid serve distinct roles in folate metabolism and clinical practice. Folic acid is widely used for supplementation and fortification due to its stability and cost-effectiveness, while folinic acid is preferred in specific medical contexts, particularly where rapid folate activity is required or folate metabolism is impaired. Understanding the differences between these two forms of vitamin B9 is crucial for optimizing their use in both preventive and therapeutic settings.
In the autism setting, it is exciting to see the potential benefits of folinic acid.
