Dr. Ron’s Research Review – July 15, 2015

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This week’s research review focuses on the safety of folate.

Folic acid (FA) intervention trials in humans are inconsistent and are not completely supportive of protective effects except in the case of neural tube defects.  Notably, folic acid is 70-85% bioavailable compared to only 50% bioavailability of folate naturally occurring in foods. (Shorter et al., 2015)

Folate is generally regarded as a harmless based on studies evaluating the safe upper limits of folate intake. A concern has been raised about the proposed ability of folate to enhance proliferation of malignant tumors. The research, however, is based on the use of anti-folates in oncology and a study. (Strickland et al., 2013)

A study was conducted within JANUS among 3000 prostate cancer cases and 3000 controls. A weak positive association was observed between folate concentration and prostate cancer risk [OR highest vs lowest quintile = 1.15 (0.97-1.37), P-trend = 0.04], which was more pronounced among individuals >/= 50 years at inclusion [OR 1.40 (1.07-1.84), P-trend = 0.02]. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]. (de Vogel et al., 2013)
Median folate as p-aminobenzoylglutamate (nmol/l) was 13.98 (8.67–23.60) for prostate cancer and 13.70 (8.65–23.40) for controls. The reference range of folate for adults is 4.5-45.3 nmol/L.
That’s a 2% difference in folate levels within the normal range (13.98- 3.70÷13.75). No p value was given in the study.

 

Dr. Ron


Articles

 

Serum folate and vitamin B12 concentrations in relation to prostate cancer risk--a Norwegian population-based nested case-control study of 3000 cases and 3000 controls within the JANUS cohort.
            (de Vogel et al., 2013) Download
BACKGROUND: Although individual studies have been inconsistent, meta-analyses of epidemiological data suggest that high folate and vitamin B12 levels may be associated with increased prostate cancer risk. METHODS: Within JANUS, a prospective cohort in Norway (n = 317 000) with baseline serum samples, we conducted a nested case-control study among 3000 prostate cancer cases and 3000 controls, matched on age and time at serum sampling, and county of residence. Using conditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk were estimated according to quintiles of serum folate, vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy) and methionine, and according to MTHFR 677C-->T genotypes. To correct for degradation during sample storage, folate concentration was measured as p-aminobenzoylglutamate (pABG) equivalents following oxidation and acid hydrolysis. RESULTS: We observed a weak positive association between folate concentration and prostate cancer risk [OR highest vs lowest quintile = 1.15 (0.97-1.37), P-trend = 0.04], which was more pronounced among individuals >/= 50 years at inclusion [OR 1.40 (1.07-1.84), P-trend = 0.02]. tHcy showed an inverse trend with risk [OR 0.92 (0.77-1.10), P-trend = 0.03]. Vitamin B12, MMA and methionine concentrations were not associated with prostate cancer risk. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]. CONCLUSION: This large-scale population-based study suggests that high serum folate concentration may be associated with modestly increased prostate cancer risk. We did not observe an association between vitamin B12 status and prostate cancer risk.

Consequences of dietary methyl donor supplements: Is more always better?
            (Shorter et al., 2015) Download
Epigenetic mechanisms are now recognized to play roles in disease etiology. Several diseases increasing in frequency are associated with altered DNA methylation. DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Increased intake of these compounds correlates with decreased neural tube defects, although this mechanism is not well understood. Consumption of these methyl donor pathway components has increased in recent years due to fortification of grains and high supplemental levels of these compounds (e.g. vitamins, energy drinks). Additionally, people with mutations in one of the enzymes that assists in the methyl donor pathway (5-MTHFR) are directed to consume higher amounts of methyl donors to compensate. Recent evidence suggests that high levels of methyl donor intake may also have detrimental effects. Individualized medicine may be necessary to determine the appropriate amounts of methyl donors to be consumed, particularly in women of child bearing age.

Molecular mechanisms underlying the potentially adverse effects of folate.
            (Strickland et al., 2013) Download
The importance of proper consumption of dietary folate for human health has been highlighted by an extensive number of publications over several decades. Fortification of grain products with folic acid was initiated with the specific intent to prevent neural tube defects, and the scope of this endeavor is unique in that its target population (women of the periconceptional period) is many times smaller than the population it affects (everyone who ingests fortified grain products). Folate fortification has been wildly successful in terms of its goal; since its inception, the incidence of neural tube defects has markedly decreased. In the wake of this public health triumph, it is important to catalog both the serendipitous benefits and potential side effects of folic acid supplementation. The vitamin is generally regarded as a harmless nutrient based on studies evaluating the safe upper limits of folate intake. In recent years, however, a concern has been raised with respect to a potential downside to folate supplementation; namely, its proposed ability to enhance proliferation of malignant tumors. The current review summarizes the available literature on the effects of folate supplementation and the molecular mechanisms by which high doses of folate may have negative consequences on human health, especially with regard to cancer.

References

de Vogel, S, et al. (2013), ‘Serum folate and vitamin B12 concentrations in relation to prostate cancer risk--a Norwegian population-based nested case-control study of 3000 cases and 3000 controls within the JANUS cohort.’, Int J Epidemiol, 42 (1), 201-10. PubMedID: 23508410
Shorter, KR, MR Felder, and PB Vrana (2015), ‘Consequences of dietary methyl donor supplements: Is more always better?’, Prog Biophys Mol Biol, 118(1-2) (1-2), 14-20. PubMedID: 25841986
Strickland, KC, NI Krupenko, and SA Krupenko (2013), ‘Molecular mechanisms underlying the potentially adverse effects of folate.’, Clin Chem Lab Med, 51 (3), 607-16. PubMedID: 23241610