Friday, 7 December 2012

Homocysteine and Glutathione Nutrients

Folate, choline, B6, and B12

All these nutrients are part of the homocysteine cycle. High blood levels of homocysteine are dangerous and greatly increase your risk of heart disease. Homocysteine can be recycled to methionine by several routes: by choline; or folate. It can also be excreted as uria after being converted to cysteine by vitamin B6.

Here are a couple of pictures of the homocysteine cycle, showing how the nutrients interact (choline is listed as it's active form 'betaine'):

Elevated homocysteine is usually treated with a low-methionine diet with limited results, just like a low cholesterol diet doesn't reduce cholesterol levels. Also as methionine is found in many nutritious foods, such as eggs and other animal foods, restricting it can lead to an unbalanced diet. Increasing choline, folate, vitamins B6 and B12 is much more effective at reducing homocysteine levels, though some are more effective than others, as we will see...

Folate versus choline: Spina Bifida

Many women eating carnivorous diets, low in folate as little to no chicken liver was eaten, have produced healthy babies free of Spina Bifida. Normally women are given folic acid supplements in early pregnancy to prevent this disease, ignoring the folate versus folic acid issue for now, if folate/folic acid is so important for preventing Spina bifida, how can healthy babies be born to a mother eating a diet very low in folate? My thoery is that choline replaces most if not all of folate's duties, as it's not folate itself but high homocysteine and low glutathione that is the real cause behind folate deficiency problems such as spina bifida.

Seems others agree: "Anomalies in homocysteine metabolism have been implicated in disorders ranging from vascular disease to neural tube birth defects such as spina bifida." (link)

Homocysteine is an amino acid derivative in the blood, high levels are associated with heart disease. The usual method for reducing it is restricting methionine as it's made from that, but this doesn't really work just like restricting cholesterol intake doesn't help blood cholesterol levels. Folate can be used to reduce homocysteine blood levels by recycling it back into methionine, and so can choline.

Folate needs B12 in order to recycle homocysteine, a normal mixed diet has very little B12 compared to a carnivore one which is why such large amounts of folate are used in supplements to prevent Spina Bifida, as much as 5mg (5,000ug) or more. The increased B12 on a carnivore diet means less folate is needed to effectively recycle homocysteine.

Similarly choline needs zinc. My menu provides ~23mg zinc, while the USDA RDA is 11mg, so it's likely less choline is needed also. Choline has many other functions though, making phospholipids and other things vital for brain development, and helps in metabolising fats so it's unlikely a lot less is needed on a carnivore diet.

Another Way Out

Apart from recycling homocysteine back into methionine, we can exit this cycle using B6, and it turns into cysteine. Add some glycine (gelatin), and glutamate (any protein) along with selenium, and they make glutathione, the body's most potent antioxidant.

In trials with homocysteinuria, a genetic disease which presents with very high levels of homocysteine and heart disease, homocysteine is successfully lowered with folate but the heart disease rate stays the same, but giving vitamin B6 instead does help the heart disease! This shows that recycling homocysteine back to methionine is of little value, to proper thing to do is turn it to cysteine, then glutathione.

I think it's not the high homocysteine itself causing the problems but the low glutathione levels. Low glutathione levels are the reason why the low protein rats in Colin T Campbell's studies just all died instead of getting cancer (link).

The WAPF reports that 3.4mg of B6 daily is needed to fully saturate B6 levels in breast milk (link), so for pregnancy I will assume a similar level is needed, and less while not pregnant. Using the ol' 'eating for two' would mean 1.7mg B6 is needed; the USDA RDA is 1.3mg normally, 1.9mg for pregnant, and 2mg for breastfeeding, proportionally if breastfeeding really needs 3.4 then normal means ~2.2mg is needed. Vitamin B6 recommendations used to be based of protein, to the tune of 0.016mg per gram of protein intake, so 1.6mg per 100g of protein. I would err on the side of caution and say that more B6 is likely better, but if there is sufficient cysteine, glycine, glutamate, and selenium in one's diet to make glutathione without needing B6/homocysteine then glutathione levels will still be high, and B6 is not as critical.

Thus I will no longer be recommending chicken liver specifically for it's folate content, and am happy that the amount of folate provided by the other liver and egg yolks is plenty (1 egg has as much folate as 2000 calories of rib eye), these foods also provide choline for alternative recycling of homocysteine.

The carnivore RDA will have a lower recommendation for folate than the USDA RDA, choline will be same or greater than USDA RDA, zinc will remain at 12x copper but likely more copper will be recommended than the USDA RDA, and B6 will be based on protein intake. There will also be emphasise on getting plenty of vitamin B12, selenium, methionine, cysteine, and glycine.

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Side Note: Folic acid versus Folate

Folic acid is the artificial form of folate, found only in supplements and added to foods such as flour. Folate is the natural form found in food. An enzyme called dihydrofolate reductase is needed to convert folic acid to folate, this enzyme is also needed to convert folate to it's active form tetrahydrofolate (THF); too much folic acid slows the synthesis of THF and can actually cause deficiency.

Conversion of folic acid to folate is low but variable (link), and excess unconverted folic acid is dangerous (link). Two genes that effect dihydrofolate reductase are: C677T and A1298C. Having these mutations decreases your ability to convert folic acid to folate.

Too much folic acid is also associated with caner, high serum levels are associated with epigenetic changes linked to bowel cancer (link), and cell grown in cultures with high levels of folic acid induces these changes. Selenium and vitamin D3 levels decreased these changes, all the more reason to eat your kidney or pork and soak up the sun. But it seems natural folate is anti-cancer: "daily supplementation of 1 mg of folic acid increased the risk of prostate cancer, while dietary and plasma folate levels among vitamin nonusers actually decreased the risk of prostate cancer" (link). Anti-folate drugs are used as a treatment for cancer (link). More info.

For these reasons I recommend getting natural folate from food rather than supplements as folic acid.

If you must take supplements, seek out one of the following, as these are true folate rather than folic acid: 5-MTHF, 5-methyltetrahydrofolic acid, l-methylfolate, levomefolic acid, folinic acid, 'Metafolin', 'Deplin', 'Quatrafolic'.

Side Note: Alternatives

The folate cycle also turns a serine into a glycine, serine is an amino acid found in egg yolks, pork liver, turkey, and to a lesser degree other livers and muscle meat, so if a large amount of folate is eaten then less glycine from gelatin is needed; so the choice is between eating gelatin or poultry liver. One or the other is needed, as glycine is a critical component of glutathione.

I don't know if high amounts of choline mean that folate isn't used to recycle homocysteine, and thus less glycine is made, so I do feel it's much less risky to eat gelatin for the glycine directly.



    In the case of mothers, the vitamin B(12) concentration was 21% lower (95% CI, 8%-33%) compared with control mothers. Unlike folate, vitamin B(6,) and homocysteine, a vitamin B(12) concentration of <or=185 pmol/L was associated with a 3.5-fold (95% CI, 1.3- 8.9) spina bifida risk. In children, no differences in folate, vitamin B(6), vitamin B(12), and homocysteine concentrations were observed after adjustment for the child's age.
    A marginal maternal vitamin B(12) status increases the risk of an offspring with spina bifida.

    I think the the methyl group can come from either serine or glycine; and glycine is also what's left when betaine (the oxidation product of choline) yields all its methyl groups. The best sources of betaine are spinach and beetroot.

    If homocysteine is the fasting source of both methionine and cysteine, then there may be a low homocysteine pathology; homocysteine can be seen as the sulfur-amino pool. It also has a role in acute phase inflammation when it becomes elevated locally and reacts with the copper in ceruloplasmin to generate ROS.

  2. I believe the actual the particular methyl class can come from sometimes serine as well as glycine; and also glycine is also what remains while betaine (your corrosion merchandise involving choline) makes all of its methyl teams. The most effective sources of betaine are spinach as well as beetroot. rs gold for saleWOW Gold Kaufen Billig

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