Impact of High-dose Folic Acid Supplementation on Pathways Linked to DNA Formation

Metabolic Consequences of High-Dose Folic Acid Supplementation on Kinetics of 1-Carbon Metabolism

Periconceptional supplementation with folic acid - the synthetic form of the B-vitamin folate - reduces the occurrence of adverse pregnancy outcomes such as spina bifida. The underlying biochemical mechanisms for how folic acid affects health outcomes however are unknown. The naturally occurring form 5-methyltetrahydrofolate (5-MTHF) is now available and discussed as an adequate substitute to folic acid. This study aims to determine the effect of folic acid compared to 5-MTHF on cellular mechanisms. Stable isotope tracer protocols will be used that allow determining the effect of folic acid on the dynamics of metabolic pathways in the human body.

Hypothesis: Supplementation with high-dose folic acid alters the turnover rate of folate dependent pathways in healthy humans; but 5-MTHF does not. Genetic variations in a key enzyme of the folate metabolism will aggravate the effect of folic acid on the metabolic pathways.

Inclusion Criteria:

• Generally healthy
• Body mass index of between 19-24 kg/m2
• Normal folate, vitamin B12, and B6 status

Exclusion Criteria:

• Unable to swallow tablets
• Unable to receive intravenous catheters
• Use of vitamin supplements, amino acid or protein supplements for more than six months before study participation
• Chronic consumption of a high-protein diet (e.g. Atkins Diet)
• Medical conditions such as diabetes, asthma, cancer, cardiovascular disease, a history of neural tube defect (such as spina bifida) affected pregnancy, have had gastrointestinal surgery, abnormal kidney, thyroid function, or psychiatric illness, or any other chronic disease
• Pregnancy or lactation
• Smoking, use of recreational drugs, and/or consumption of more than one alcohol drink per day or more than seven per week.
• Use of long-term prescription medication such as hormonal contraceptives, antidepressants, anticonvulsants, anticoagulants, or other chronic medication
• Blood donation in the last three months prior to study start
• Unable to provide informed consent, or unable to read and write English
• Low compliance to intervention as determined by early steady-state or reduction in blood folate concentrations