2% enzyme activity. Everyone.
Human liver DHFR has less than 2% of the activity found in rats. This means our capacity to process synthetic folic acid is inherently poor - regardless of MTHFR status. The problem isn't your genes. It's the synthetic form.
DHFR is the bottleneck - not MTHFR.
MTHFR mutations don't prevent folic acid processing. DHFR (dihydrofolate reductase) is the enzyme responsible for converting folic acid. But DHFR activity in humans is extremely limited.
Step 1: DHFR Conversion
Folic acid (synthetic) → dihydrofolate → tetrahydrofolate (THF)
Step 2: Transformation
THF undergoes various transformations to 5,10-methylenetetrahydrofolate
Step 3: MTHFR Conversion
5,10-methyleneTHF → 5-methyltetrahydrofolate (5-MTHF) - the active form
Key finding: Doses of folic acid as low as 200mcg can lead to unmetabolized folic acid (UMFA) in the bloodstream. Yet a single serving of fortified breakfast cereal can contain up to 400mcg.
Unmetabolized folic acid accumulates.
Of older adults have detectable UMFA
Average UMFA as portion of total serum folate
Receptor Competition
UMFA competes with natural 5-MTHF for folate transporters and receptors, potentially creating functional folate deficiency despite adequate intake.
Immune Dysfunction
UMFA may inhibit MAIT cells and natural killer cells, potentially affecting immune surveillance and cancer prevention.
Masking B12 Deficiency
High folic acid can mask megaloblastic anemia from B12 deficiency, allowing neurological damage to progress undetected.
Binding Affinity
Folic acid has the highest binding affinity for all folate receptors, potentially blocking transport and utilization of active folates.
MTHFR variants compound the problem.
While people with MTHFR mutations can technically process folic acid, the C677T variant reduces MTHFR activity by 35-70%, creating an additional bottleneck. Combined with DHFR's already poor function, this creates multiple points of impairment.
Reduced enzyme activity in approximately 40-60% of populations.
Significantly reduced activity through thermolability and faster FAD cofactor loss.
High doses of folic acid can paradoxically increase homocysteine levels - the opposite of what we want from folate supplementation.
MTHFR variants aren't defects.
The high frequency of MTHFR variants (40-60% of populations) suggests they're not simply defects. Research links MTHFR variant frequency to UV radiation exposure, with higher rates in populations from high-UV environments.
Potential Evolutionary Advantages
- Enhanced DNA synthesis quality
- Protection against certain cancers
- Folate conservation during scarcity
- Adaptation to high-folate diets
The mismatch: The problem isn't the variants themselves - it's the mismatch between our evolved biology and the modern environment flooded with synthetic folic acid.
A more nuanced approach.
Consider Folinic Acid or 5-MTHF
5-MTHF doesn't require DHFR conversion, doesn't create UMFA, and is immediately bioavailable.
Be Aware of Fortified Foods
In countries with mandatory fortification, many people already consume significant folic acid without realizing it.
Support Overall Methylation
Adequate B12, B6, and riboflavin are crucial. Don't forget Betaine (TMG), choline, and glycine for the other half of methylation.
Individual Assessment
Those with digestive issues, multiple MTHFR variants, or chronic health conditions may be more susceptible to UMFA accumulation.
It may be time to reconsider.
Researchers increasingly suggest that folinic acid or 5-MTHF should replace folic acid in supplementation - not because people can't process folic acid at all, but because our bodies process it poorly, and this inefficiency may have consequences we're only beginning to understand.
MTHFR for Beginners
Understanding methylation, genetic variants, and why MTHFR isn't the problem you think it is.