Homocysteine Reduction-2

TMG and Zinc: Bringing Homocysteine Under Control

Other nutrients that encourage the remethylation of homocysteine include TMG and zinc, both of which enhance the action of B vitamins.

TMG operates along a different pathway than the B vitamins. In fact, some individuals who have a severely elevated homocysteine level respond only to TMG because its activity is limited to the liver and kidneys. To decrease a severely elevated homocysteine level, repeated high doses of TMG must be taken throughout the day. One small study found that TMG supplementation taken concurrently with vitamin B6 and folic acid significantly reduced homocysteine (Dudman NP et al 1996).

Zinc acts in concert with vitamin B6 to promote remethylation of homocysteine to methionine. Zinc is also needed for the conversion of homocysteine to cysteine and glutathione. (For safety information on zinc, see the Safety Caveats section at the end of this chapter.)

For More Information
To learn more about the conditions associated with hyperhomocysteinemia, see the following chapters:

Congestive Heart Failure
Atherosclerosis
Managing High Blood Pressure
Diabetes
Thyroid Disorders


Removing Excess Homocysteine
While the remethylation pathway recycles homocysteine back into methionine, the transsulfuration pathway removes it. In the transsulfuration pathway, homocysteine is condensed with serine to form cystathionine, which is converted into cysteine. In turn, cysteine is converted into glutathione, taurine, and sulfate waste products that are flushed from the body in urine. All of these reactions occur with the help of vitamin B6.

Besides vitamin B6, other nutrients that strengthen the transsulfuration of homocysteine include:

SAMe—
SAMe is derived directly from methionine. Its job is to provide methyl groups for reactions throughout the body, including the methylation of nucleic acids (RNA and DNA), proteins, and structures throughout the brain. SAMe is the precursor to such nutrients as creatine, glutathione, taurine, L-carnitine, and melatonin and can be found in almost every tissue in the body. It has been studied in the treatment of depression, schizophrenia, demyelination diseases, liver disease, dementia, arthritis, and other conditions. It is also necessary for normal circadian rhythms. High doses of SAMe, 1600 milligrams (mg) daily, increased phosphocreatine levels in the human brain (Silveri MM et al 2003), indicating that SAMe is important in forming creatine. Although SAMe is part of the methionine cycle, taking supplemental SAMe does not increase the production of homocysteine (Devlin TM 2001). It does, however, encourage the conversion of homocysteine to cysteine and glutathione (Devlin TM 2001), thus lowering homocysteine levels. (For safety information on SAMe, see the Safety Caveats section at the end of this chapter.)
Selenium—The trace mineral selenium is necessary for the antioxidant activity of glutathione, which is converted from homocysteine. Selenium deficiency has been shown to increase oxidative damage in animals. By boosting selenium levels, you can raise your level of glutathione and help lower your homocysteine level (Devlin TM 2002).

N-acetyl-cysteine—
Consuming N-acetyl-cysteine may reduce homocysteine levels by encouraging the production of cysteine, which is critical to the conversion of homocysteine to glutathione. By increasing the production of cysteine, it may be possible to boost the amount of homocysteine converted into glutathione.
Cysteine—Like N-acetyl-cysteine, cysteine supplementation may prevent the release of stored homocysteine into the bloodstream. The Life Extension Foundation favors maintaining an adequate level of cysteine to maintain normal glutathione levels.

Inhibiting the Formation of Homocysteine
Not all the homocysteine created is released directly into the bloodstream as free homocysteine. In fact, less than 1 percent of the homocysteine in the blood is free. The majority, about 98 to 99 percent, is bound to proteins in the blood and considered stored.

This store of homocysteine may be released in response to decreased methylation or oxidative damage, or in response to other influences. Nutrients that have been shown to inhibit the release of homocysteine include:

Creatine—
Somewhere between 50 and 90 percent of the SAMe required by the body goes into the production of creatine (Devlin TM 2001; Finkelstein JD et al 1984; Lee H et al 1998; Silveri MM et al 2003; Stead LM et al 2001). Supplementation with creatine diminishes the need for SAMe, reduces formation of homocysteine, and the need for homocysteine remethylation. In animal studies, supplementation with creatine for 2 weeks reduced homocysteine levels by 25 percent (Stead LM et al 2001).

Choline-producing nutrients—
SAMe is involved in the production of choline. By taking choline-producing nutrients, your body produces less SAMe, which reduces the amount of homocysteine needed. Choline-producing nutrients include cytidine diphosphate (CDP) choline, lecithin, alpha-glycerylphosphorylcholine, and choline chloride.

Life Extension Foundation Recommendations

It is important to begin your homocysteine-lowering program by working with a qualified physician and taking the necessary blood tests to evaluate your risk. To help lower your homocysteine level, the Life Extension Foundation suggests:

Folic acid—4000 to 8000 mcg daily
Vitamin B12—1 to 2 mg daily
Vitamin B6—100 to 200 mg daily
SAMe—400 mg two to four times daily
TMG—2 to 4 grams daily
Zinc—30 to 90 mg daily
CDP choline—250 to 500 mg daily. Alternatively, you can use 1 to 3 teaspoons of liquid choline chloride daily mixed with 2 ounces of juice, 1 tablespoon of pure lecithin granules daily, or 250 mg of a-GPC daily.
Micronized creatine—500 mg (in capsule form) four to eight times daily
N-acetyl-cysteine—600 mg (in capsule form) one to two times daily on an empty stomach
If this protocol is not successful at lowering homocysteine level, a weekly 1-mg vitamin B12 injection may be necessary (this requires a prescription).


Hyperhomocysteine Safety Caveats
An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:

Creatine
Do not take creatine if you have diabetes, kidney failure, a kidney disorder such as nephrotic syndrome, or are otherwise at risk of having a kidney disorder.
If you take creatine, have your serum creatinine level monitored frequently.
Creatine can cause muscle cramping, muscle strains, and gastrointestinal symptoms such as nausea and diarrhea.
Folic acid

Consult your doctor before taking folic acid if you have a vitamin B12 deficiency.
Daily doses of more than 1 milligram of folic acid can precipitate or exacerbate the neurological damage caused by a vitamin B12 deficiency.

NAC
NAC clearance is reduced in people who have chronic liver disease.
Do not take NAC if you have a history of kidney stones (particularly cystine stones).
NAC can produce a false-positive result in the nitroprusside test for ketone bodies used to detect diabetes.
Consult your doctor before taking NAC if you have a history of peptic ulcer disease. Mucolytic agents may disrupt the gastric mucosal barrier.
NAC can cause headache (especially when used along with nitrates) and gastrointestinal symptoms such as nausea and diarrhea.

Phosphatidylcholine
Phosphatidylcholine can cause increased salivation, a metallic taste, headache, drowsiness, and gastrointestinal symptoms such as nausea and diarrhea
SAMe

Consult your doctor before taking SAMe if you have bipolar disorder. See your doctor frequently if you take SAMe and you have bipolar disorder.
Consult your doctor before taking SAMe if you take antidepressants. See your doctor frequently if you take SAMe in place of or in addition to antidepressants.
Consult your doctor before taking SAMe if you have cancer. Nucleic acid methylation patterns may change in people who have cancer and take SAMe.
Do not take SAMe if you are undergoing gene therapy.
SAMe can cause anxiety, hyperactive muscle movement, insomnia, hypomania, and gastrointestinal symptoms such as nausea and diarrhea

Trimethylglycine (betaine)
Do not take trimethylglycine (betaine) if you have gastritis, gastroesophageal reflux disease (GERD), or peptic ulcer disease.
Vitamin B6

Do not take 5 milligrams or more of vitamin B6 daily if you are being treated with levodopa, unless you are taking carbidopa at the same time.

Vitamin B12 (cyanocobalamin)
Do not take cyanocobalamin if you have Leber's optic atrophy.

Zinc
1)High doses of zinc (above 30 milligrams daily) can cause adverse reactions.
2)Zinc can cause a metallic taste, headache, drowsiness, and gastrointestinal symptoms such as nausea and diarrhea.
3)High doses of zinc can lead to copper deficiency and hypochromic microcytic anemia secondary to zinc-induced copper deficiency.
4)High doses of zinc may suppress the immune system.