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Review
. 2023 Nov 6;15(21):4699.
doi: 10.3390/nu15214699.

Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review

Ali M Fardous  1 , Ahmad R Heydari  1   2
Affiliations
Review

Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review

Ali M Fardous et al. Nutrients. .

Abstract

This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.

Keywords: aging; carcinogenesis; embryogenesis; epigenetic; folate; folic acid; methylation; neurodevelopment; one-carbon cycle; unmetabolized folic acid (UMFA).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Implications of excess folic acid: impact on multifaceted pathways and their biological consequences.
Figure 2
Figure 2
Potential biochemical impact of excess folate on one-carbon metabolism pathways. The question marks and dotted blue line represent the potential molecular targets of excess folate and/or UMFA on one-carbon meatbolic enzymes and biosynthetic outputs.
See this image and copyright information in PMC

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