Methyl & MTHFR.

[pjoshea13]

Tom67inMA raised this issue in the "Methyl Donor Micronutrients that Modify DNA Methylation and Cancer Outcome" thread:

"I have an MTHFR gene defect (as does about half of the US population), and my GP has recommended methylated folate and TMG supplementation to reduce my homocysteine. Does this still make sense post diagnosis?"

Studies of methyl intake & cancer risk can be confusing. That is mostly because:

- cellular hypomethylation, due to methyl deficiency, can lead to DNA instability & increased risk for cancer, whereas:

- hypermethylation, favored by some cancers, can silence protective anti-cancer genes & increase mortality risk.

One might say that in PCa, we want to have methyl sufficiency before cancer develops, & insufficiency thereafter.

Most men are unaware of their methyl status unless homocysteine is elevated, in which case adjustment of dietary B vitamins might lower levels.

For those with a major MTHFR gene defect, it's a little more complicated.

Cells receive their methyl from SAM [SAMe] & this leaves homocysteine. Homocysteine can be recycled back to SAM (via methionine) if there is dietary methyl available (primarily from folate). This requires an enzyme: Methylene tetrahydrofolate reductase (MTHFR). The gene that encodes the enzyme comes in different flavors. I tend to view common genetic variants (polymorphisms) as being natural, rather than as defects, but there can be health consequences. Anyway, the variant that concerns us is the C677T.

"About ten percent of the North American population are T-homozygous for this polymorphism." "Individuals of 677TT are predisposed to mild hyperhomocysteinemia (high blood homocysteine levels), because they have less active MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine)." [1]

From a 2015 meta-analysis [2]:

"... the protective effect of homozygote TT against high aggressive PCa was proved to have significant difference."

It's not much to go on, but I'd be cautious in addressing elevated homocysteine due to C677T.

-Patrick

[1] en.wikipedia.org/wiki/Methy...

[2] ncbi.nlm.nih.gov/pubmed/258...

[cujoe]

Every time I see reference to the MTHFR gene I can't help adding in some additional letters. If it is defective in half the population, maybe the added letters are appropriate.

[NPfisherman in reply to cujoe]

That's how I feel about the beast we have inside...MTHRFKR gene... send that gene to the depths of hades...

[NPfisherman]

In short, we should avoid or eat very limited amounts of fortified cereals, breads with folic acid, B12 etc added, and other grain products in a nutshell?? Correct??

Fish

[pjoshea13 in reply to NPfisherman]

Fish,

More or less. Avoid anything that says "Folic acid" on the label. -Patrick

Baked goods will have something like this:

"INGREDIENTS: Enriched Wheat Flour (Wheat Flour, Malted Barley Flour, Niacin, Iron, Thiamin Mononitrate, Riboflavin, Folic Acid)" ......

Is it possible to buy wheat flour in the U.S. that is not 'enriched'? Is it illegal to sell it?

[GeorgeGlass in reply to pjoshea13]

Patrick, I'm trying to save my tendons after Levaquin poisoning but I dont want to take collagen Type I and III because they have glutamine and another item that can spread PCx. I am considering Niacinamide and TMG to help with slowing the Levaquin detruction on my mitochondria in the tendons. I'm also taking proline, lysine, arginine, glycine and MSM. Do you see any concern with any of these items related to my advanced PCx? I'm most concerned with the TMG, niacinamide and slightly concerned about the arginine and glycine.

thanks,

George

[tom67inMA]

Interesting. After double checking my test results, I have "a single copy of the C677T mutation", so heterogeneous with one "good" copy and one "bad" copy.

And it turns out my original understanding was backwards, as I always thought methylfolate was folate with a methyl group added by the MTHFR enzyme. But it sounds like it's actually removing a methyl group and making it available.

And for what it's worth, my homocysteine level when last checked in 2017 was at 9.9. That's normal according to the lab's reference range but high according to my doctor. In any case, it's not at a level that implies I'll have a heart attack tomorrow.

[Kuanyin]

The Role of Metformin on Vitamin B Deficiency: A Meta-analysis Review

Abstract

Background: Metformin is the only biguanide oral hypoglycemic drug, which is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). Objectives: To systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. Methods: A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low risk and high risk bias were also conducted. Results: 29 studies were selected with a total of 8089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR= 2.45, 95% CI, 1.74-3.44, P< 0.0001). Heterogeneity was relatively high (I2= 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference= -65.8, 95% CI, -78.1 to -53.6 pmol/L, P< 0.00001) with high heterogeneity (I2=98%), and low publication bias. RCTs analysis of with low and high risk group revealed similar trends. Conclusions: We concluded that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.

Article in Internal and Emergency Medicine 10(1):93-102 · February 2015 with 721 ReadsDOI: 10.1007/s11739-014-1157-5

1 A couple of times during the past years, I have been forced (mainly because the regular form, rather than the ER Osmotic, tears the hell out of my stomach) to temporarily discontinue taking Metformin. One immediate result was a significant drop in my homocysteine numbers.

2 Is it possible that while our blood serum measures satisfactory levels of free, circulating VB12, it is not actually being absorbed.?

In my situation, I feel that Metformin is the main contributor to my homocysteine problem. This places me in a dilemma regarding how to proceed. I take a product called Methyl B Complex (Ortho Molecular Products).

[cujoe in reply to Kuanyin]

Wondering if herbal similar-to-metformin, berberine, has the same issue re: Vit B-12??

[Bill2544]

Thanks to you for your Methyl & MTHFR post, Patrick, and to others who have posted on this subject. I recently discovered that I have two copies of the MTHFR C677T mutation (homozygous) => a history of stubbornly high homocysteine despite carefully following the recommended supplement/dietary regimens. Only after pressing my cardiologist to order the genetic test did the underlying reason become clear. I now take LEF's Homocysteine Resist (5g L-5-methyltetrahydrofolate calcium salt plus 1mg methylcobalamin) with only modest improvement @ 1/day.

Given my low and very slowly advancing PSA (0.28) and your caution "I'd be cautious in addressing elevated homocysteine due to C677T", does this sound reasonable to you and others or are there better regimens?

[Bill2544 in reply to Bill2544]

Correction: LEF's Homocysteine Resist contains 5000 mcg L-5-methyltetrahydrofolate and 1000 mcg methylcobalamin.

[pjoshea13 in reply to Bill2544]

Bill,

I doubt that there many PCa doctors who could advise you, & I'm not going to try, but I like the sound of "modest improvement".

-Patrick

[j-o-h-n]

Methyl & MTHFR, weren't they a comedy team in vaudeville?

Good Luck, Good Health and Good Humor.

j-o-h-n Monday 03/18/2019 1:35 PM DST

[wise-crow]

Just wondering... if toxic dentistry practice, by the placing of mercury-amalgam fillings, and others (root canals & metals placed in the mouth in any way) in either the individual or their parents, has contributed to this gene mutation??