Dr. Ron’s Research Review – March 11, 2015

©                                                                                                                 

This week’s research review focuses on Folate vs Folic Acid.

Bailey and Ayling suggested that humans have an extremely slow and variable activity of liver dihydrofolate reductase; therefore, individuals who possess lower than average activity may have difficulty converting high intakes of folic acid to biologically active forms. (Bailey and Ayling, 2009) (Bailey et al., 2010)

Unmetabolized folic acid (FA) appears in the circulation at doses of >200 μg. Individuals show wide variations in their ability to reduce FA. (Obeid et al., 2013) (Obeid et al., 2011)

5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase. (Prinz-Langenohl et al., 2009)

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. (Lamers et al., 2006)

A pharmacokinetic study demonstrated that oral 5-MTHF has higher bioavailability compared to folic acid, irrespective of the patient's genotype. (Willems et al., 2004)

 

Dr. Ron


 

Articles

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake
            (Bailey and Ayling, 2009) Download
Numerous clinical trials using folic acid for prevention of cardiovascular disease, stroke, cognitive decline, and neural tube defects have been completed or are underway. Yet, all functions of folate are performed by tetrahydrofolate and its one-carbon derivatives. Folic acid is a synthetic oxidized form not significantly found in fresh natural foods; to be used it must be converted to tetrahydrofolate by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans. Here we show, using a sensitive assay we developed, that the reduction of folic acid by DHFR per gram of human liver (n = 6) obtained from organ donors or directly from surgery is, on average, less than 2% of that in rat liver at physiological pH. Moreover, in contrast to rats, there was almost a 5-fold variation of DHFR activity among the human samples. This limited ability to activate the synthetic vitamer raises issues about clinical trials using high levels of folic acid. The extremely low rate of conversion of folic acid suggests that the benefit of its use in high doses will be limited by saturation of DHFR, especially in individuals possessing lower than average activity. These results are also consistent with the reports of unmetabolized folic acid in plasma and urine.

Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States.
            (Bailey et al., 2010) Download
BACKGROUND: Unmetabolized serum folic acid (UMFA) has been detected in adults. Previous research indicates that high folic acid intakes may be associated with risk of cancer. OBJECTIVE: The objective was to examine UMFA concentrations in relation to dietary and supplemental folate and status biomarkers in the US population aged > or =60 y. DESIGN: Surplus sera were analyzed with the use of data from the National Health and Nutrition Examination Survey (NHANES) 2001-2002, a cross-sectional, nationally representative survey (n = 1121). RESULTS: UMFA was detected in 38% of the population, with a mean concentration of 4.4 +/- 0.6 nmol/L (median: 1.2+/- 0.2 nmol/L). The group with UMFA (UMFA+) had a significantly higher proportion of folic acid supplement users than did the group without UMFA (60% compared with 41%). UMFA+ men and women also had higher supplemental and total (food + supplements) folic acid intakes than did their counterparts without UMFA. Forty percent of the UMFA+ group was in the highest quartile of total folic acid intake, but total folic acid intake was only moderately related to UMFA concentrations (r(2) = 0.07). Serum folate concentrations were significantly higher in the UMFA+ group and were predictive of UMFA concentrations (r(2) = 0.15). Serum 5-methyltetrahydrofolate and vitamin B-12 concentrations were higher in the UMFA+ group, whereas there was no difference between the 2 UMFA groups in red blood cell folate, serum homocysteine, or methylmalonic acid concentrations. CONCLUSIONS: Approximately 40% of older adults in the United States have UMFA that persists after a fast, and the presence of UMFA is not easily explained in NHANES by folic acid intakes alone. Given the possibility that excessive folic acid exposure may relate to cancer risk, monitoring of UMFA may be warranted.

Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age
            (Lamers et al., 2006) Download
BACKGROUND: For the primary prevention of neural tube defects (NTDs), public health authorities recommend women of childbearing age to take 400 mug folic acid/d 4 wk before conception and during the first trimester. The biologically active derivate [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) could be an alternative to folic acid. OBJECTIVE: We investigated the effect of supplementation with [6S]-5-MTHF compared with that of folic acid on red blood cell folate concentration, an indicator of folate status. DESIGN: The study was designed as a double-blind, randomized, placebo-controlled intervention trial. Healthy women (n = 144) aged 19-33 y received 400 microg folic acid, the equimolar amount of [6S]-5-MTHF (416 microg), 208 microg [6S]-5-MTHF, or placebo as a daily supplement for 24 wk. Red blood cell and plasma folate concentrations were measured at baseline and at 4-wk intervals. RESULTS: The increase in red blood cell folate over time was significantly higher in the group receiving 416 microg [6S]-5-MTHF/d than in the groups receiving 400 microg folic acid/d or 208 microg [6S]-5-MTHF/d (P < 0.001). No plateau was reached in red blood cell folate concentration in the 3 treatment groups during 24 wk of intervention; however, plasma folate plateaued after 12 wk. CONCLUSIONS: We showed that administration of [6S]-5-MTHF is more effective than is folic acid supplementation at improving folate status. In addition, the study indicates that the recommended period for preconceptional folic acid supplementation should be extended to >4 wk for maximal prevention of NTDs based on folate concentrations. [6S]-5-MTHF might be an efficient and safe alternative to folic acid.


 

Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults
            (Obeid et al., 2011) Download
Folate deficiency can cause age-related disease. Folic acid (FA) has been used in studies aiming at disease prevention. Recently, unmetabolized FA in plasma raised public health concerns; but numerous studies used FA for disease prevention. Concentrations of the folate forms FA, 5-methyltetrahydrofolate (5-MTHF), and tetrahydrofolate (THF) were measured before and after 3-week placebo or FA 5 mg, vitamin B6 40 mg, and cyanocobalamin 2 mg per day administrated to 74 older adults (median age, 82 years). Concentrations of 5-MTHF and total homocysteine (tHcy) (r = -0.392) and S-adenosylmethionine (r = 0.329) were correlated at baseline. Twenty-six percent of the elderly subjects had unmetabolized FA in plasma at the start, and concentrations of FA were increased after 3 weeks of FA treatment (median FA = 0.08 nmol/L at baseline and 15.3 nmol/L at the end of the treatment in the vitamin group). Folic acid caused a 10- and a 5-fold increase in 5-MTHF and THF, respectively, and lowered tHcy (median tHcy = 17.2 mumol/L at baseline vs 9.0 mumol/L after treatment). Concentrations of unmetabolized FA were positively related to those of 5-MTHF and THF. People showed wide variations in folate forms at baseline, but these were reduced after FA treatment. Folic acid given to older adults is mostly converted to THF and 5-MTHF and lowered concentrations of tHcy, but caused a substantial increase in unmetabolized FA in the plasma.

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?
            (Obeid et al., 2013) Download
Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of >200 mug. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase.
            (Prinz-Langenohl et al., 2009) Download
BACKGROUND AND PURPOSE: 5,10-Methylenetetrahydrofolate reductase (MTHFR) is responsible for the synthesis of 5-methyltetrahydrofolate (5-MTHF). The 677C-->T mutation of MTHFR reduces the activity of this enzyme. The aim of this study was, first, to compare pharmacokinetic parameters of [6S]-5-MTHF and folic acid (FA) in women with the homozygous (TT) and wild-type (CC) 677C-->T mutation, and second, to explore genotype differences. The metabolism of [6S]-5-MTHF and FA was evaluated by measuring plasma folate derivatives. EXPERIMENTAL APPROACH: Healthy females (TT, n= 16; CC, n= 8) received a single oral dose of FA (400 microg) and [6S]-5-MTHF (416 microg) in a randomized crossover design. Plasma folate was measured up to 8 h after supplementation. Concentration-time-profile [area under the curve of the plasma folate concentration vs. time (AUC)], maximum concentration (C(max)) and time-to-reach-maximum (t(max)) were calculated. KEY RESULTS: AUC and C(max) were significantly higher, and t(max) significantly shorter for [6S]-5-MTHF compared with FA in both genotypes. A significant difference between the genotypes was observed for t(max) after FA only (P < 0.05). Plasma folate consisted essentially of 5-MTHF irrespective of the folate form given. Unmetabolized FA in plasma occurs regularly following FA supplementation, but rarely with [6S]-5-MTHF. CONCLUSIONS AND IMPLICATIONS: These data suggest that [6S]-5-MTHF increases plasma folate more effectively than FA irrespective of the 677C-->T mutation of the MTHFR. This natural form of folate could be an alternative to FA supplementation or fortification.

 

 


References

Bailey, RL, et al. (2010), ‘Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States.’, Am J Clin Nutr, 92 (2), 383-89. PubMedID: 20573790
Bailey, S. W. and J. E. Ayling (2009), ‘The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake’, Proc Natl Acad Sci U S A, 106 (36), 15424-29. PubMedID: 19706381
Lamers, Y., et al. (2006), ‘Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age’, Am J Clin Nutr, 84 (1), 156-61. PubMedID: 16825690
Obeid, R, W Holzgreve, and K Pietrzik (2013), ‘Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?’, J Perinat Med, 41 (5), 469-83. PubMedID: 23482308
Obeid, R., et al. (2011), ‘Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults’, Metabolism, 60 (5), 673-80. PubMedID: 20727555
Prinz-Langenohl, R, et al. (2009), ‘[6S]-5-methyltetrahydrofolate increases plasma folate more effectively than folic acid in women with the homozygous or wild-type 677C-->T polymorphism of methylenetetrahydrofolate reductase.’, Br J Pharmacol, 158 (8), 2014-21. PubMedID: 19917061
Willems, FF, et al. (2004), ‘Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate and folic acid in patients with coronary artery disease.’, Br J Pharmacol, 141 (5), 825-30. PubMedID: 14769778