Foods/Supplements-Vitamins: Folate

Folate, vitamin B9, is found in leafy green vegetables, as the name suggests, although there are other food sources too. However, a significant percentage of the U.S. population was deemed to be deficient by the FDA, which intervened & mandated that grains be fortified with folic acid, effective 1/1/1998.

Folic acid fortification was introduced to prevent neural tube defects in babies. Folic acid is one of the vitamins that pregnant women typically take, but folate status during the first month is most important, i.e. when a woman might not know she is pregnant.

Folic acid converts to folate to some degree in the body, but this synthetic form, which is unnatural to the body, persists unchanged:

"{The} 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 {dihydrofolate reductase}, especially in individuals possessing lower than average activity. These results are also consistent with the reports of unmetabolized folic acid in plasma and urine." [1]

Dietary fortification with folic acid did not solve the neural tube problem. Cases did drop, but by only 25%. Everyone involved declared victory, although some claim that the fortification level is too low.

The intervention was extraordinary, in that all males, female children & women past child-bearing age or inclination, were forced to ingest folic acid regardless of folate status. And with no limitation on dose. Those who eat a lot of bread, rice or baked goods, potentially get a large dose. Curiously, after the FDA move, multivitamin formulas were not adjusted (that I could tell.)

Many countries followed the U.S. lead. Some of them with serious folate deficiencies. This is where the law of unexpected consequences showed up. Take Chile [2]:

"... colon cancer in Chile before and after the start of the mandatory flour fortification program with 220 microg of synthetic folic acid/100 g of wheat flour."

"... two study periods, 1992-1996, before folic acid fortification and 2001-2004, after the flour fortification with folic acid was established in the country"

"The highest rate ratio between the two periods was for colon cancer in the group aged 45-64 years (rate ratio: 2.6 ...) and in the 65-79 years (rate ratio: 2.9 ...)"

The reason is very simple. Folate is the main dietary methyl donor. Hypomethylation (low availability of methyl in cells) can cause DNA instability - & potentially, cancer. However, when cancer is present, hypermethylation (excessive uptake by cancer cells) can silence tumor suppressor genes. The unfortunate cancer victims (& victim is the correct term) had cancer that might never have amounted to anything. The methyl in the folic acid took away the very thing that was keeping the cancer silent.

Although many countries followed the U.S. example, many countries did not, including Norway:

[3] (2009 - Norwegian Vitamin Trial & Western Norway B Vitamin Intervention Trial)

"A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007."

"Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721)."

"341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21 ..."

"A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18 ...)"

"Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12)."

"Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods."

[4] (2015 - U.K., U.S., France, Germany, Spain, Greece, Sweden, Norway, Finland, Netherlands & Malaysia)

"Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls"

"Folate and vitamin B12 are essential for maintaining healthy patterns of DNA methylation, repair, and synthesis, and low availability of these vitamins may influence cancer development through altered methylation patterns. However, a meta-analysis of prospective studies published up to 2009 reported that higher concentrations of folate and vitamin B12 were associated with a modest increase in prostate cancer (PCa) risk."

"... the finding that a higher folate concentration was associated with an increased risk of high-grade disease but not low grade-disease suggests that the possible role of folate in PCa progression warrants further investigation."

"The role that circulating concentrations of folate might play in risk of high-grade disease and, to a lesser extent, advanced stage and aggressive disease is unclear."

"Higher folate concentration was associated with an increased risk of high-grade disease that was not evident for low-grade disease. This finding suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation."

I find it strange that in 2015, someone could be puzzled by the association.

Folate is the major methyl donor, used together with B12, to reconstitute methionine from homocysteine. Methionine is quickly converted to SAM (SAMe), which drops off its methyl to any cell that wants it. PCa cells have a greater uptake, & hypermethylation silences protective genes.

The only men affected were those not already hypermethylated. In those men, supplementation acted as a cancer accelerant.

VITAMIN B12 & Intrinsic Factor.

B12 is an essential cofactor in the SAM system. It doesn't matter what the folate status is, if there is B12 deficiency.

Intrinsic Factor [IF] is produced by parietal cells in the stomach. IF is a glycoprotein that is necessary for oral B12 to be taken up in the small intestine. There are various reasons why IF production might be impaired. Age is purportedly one, but that doesn't explain much. Alcohol intake is another, & probably the reason why my B12 status is poor.

One sign of B12 deficiency is elevated homocysteine. High levels of homocysteine indicate that the SAM system isn't working well. B12 insufficiency is just one of the possible causes. A hair mineral test might indicate a B12 issue. Mine showed no cobalt. & so I was given a small bottle of B12 & a quantity of syringes & given a lesson in injecting into belly fat.

There was a profound effect on PSA over a 4 month period, so I stopped doing that & discovered that an impaired SAM system can be protective in PCa.

In the U.S., the FDA has removed our ability to limit folate. We can stop using grain products (including rice - the more exotic grains are still not fortified). Alternatively, we can target B12.

Vegetarians/vegans are in the best position to limit B12, since it is only naturally present in animal products. However, for a man who has recently become vegan, it can take quite a while for B12 reserves to run low.

Men with impaired B12 uptake could avoid or restrict corrective actions. Certainly, avoid supplements (sublingual or otherwise.)

DEMETHYLATION.

Note that methylation of the promoter regions for tumor suppressor genes, is an epigenetic change. No genes are harmed. Epigenetic changes can be reversed.

Michael Carducci at Johns Hopkins ran a "study of Disulfiram in Men with Non-metastatic Recurrent Prostate Cancer" [5].

"... preclinical work by our group established that disulfiram ... could lead to DNA demethylation in PCa cells"

"Epigenetic changes in prostate cancer (PCa) are recognized as occurring at the earliest phase of carcinogenic transformation. Further, alterations in the epigenome persist and evolve during invasion, metastasis and progression. One of the most recognized epigenetic alterations, methylation of cytosines in gene promoter regions, can lead to tumor suppressor gene silencing and in turn contribute to the cancer phenotype. DNA methyltransferases (DNMTs) constitute the group of enzymes responsible for maintaining these CpG methylation marks, and have been the primary target of drugs developed as demethylating agents.1 Two nucleoside DNMT inhibitors, azacitidine and decitabine, are currently approved for the treatment of myelodysplastic syndrome. Their extensive incorporation into DNA may in theory lead to increased toxicity and carcinogenesis."

The results were disappoining: "Disulfiram may lead to transient demethylating changes in a subset of patients, with those who achieve higher disulfiram metabolite (MeDDC) levels more often displaying evidence of demethylation. We also found that disulfiram’s use at high-doses was significantly limited due to toxicity." "{The} lack of robust activity coupled with the high rates of toxicity seen at the higher dose leaves us unable to recommend future study of disulfiram in this patient population."

DEMETHYLATION - natural products.

Note that demethylation has to be coupled with a restriction on methyl donor intake (importantly, folic acid) or cofactor B12.

[6] Genistein.

Genistein is a phytoestrogen found in soy.

PCa & Bca studies have found a biphasic effect: stimulation at low levels; cell death at high levels. For that reasoin, I avoid physiological levels from food. LEF has a high-dose supplement [6a].

[6b] "Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells."

[6c] "Genistein reverses hypermethylation and induces active histone modifications in tumor suppressor gene B-cell Translocation Gene 3 (BTG3) in prostate cancer"

[6d] "All studied promoters, with the exception of that for BRCA1, were strongly methylated without treatment. After treatment by phytoestrogens, demethylation of GSTP1 and EPHB2 promoter regions was observed and an increase in their protein expression was demonstrated by immunohistochemistry."

[6e] "Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells"

[7] Curcumin.

[7a] "we showed that {Curcumin} reversed the methylation status of the first 5 CpGs in the promoter region of the Nrf2 gene."

[7b] "when human prostate LNCaP cells were treated with CUR, it led to demethylation of the first 14 CpG sites of the CpG island of the Neurog1 gene"

[8] Sulforaphane.

[8a] "{Sulforaphane} treatment led to demethylation of the first 5 CpGs in the promoter region of the Nrf2 gene"

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] ncbi.nlm.nih.gov/pubmed/191...

[3] ncbi.nlm.nih.gov/pubmed/199...

[4] sciencedirect.com/science/a...

[5] ncbi.nlm.nih.gov/pmc/articl...

[6a] lifeextension.com/Vitamins-...

[6b] onlinelibrary.wiley.com/doi...

[6c] ncbi.nlm.nih.gov/pmc/articl...

[6d] ncbi.nlm.nih.gov/pubmed/206...

[6e] ncbi.nlm.nih.gov/pmc/articl...

[7a] ncbi.nlm.nih.gov/pubmed/217...

[7b] ncbi.nlm.nih.gov/pmc/articl...

[8a] ncbi.nlm.nih.gov/pmc/articl...

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