Betaine - Monograph

Alternative Medicine Review, May, 2003

Introduction

Betaine (trimethylglycine), the trimethylated compound of the amino acid glycine, is an essential biochemical component of the methionine/homocysteine cycle. Betaine acts as a donor of methyl (C[H.sub.3]) groups and, as such, is often used as a nutritional supplement to lower plasma homocysteine levels, and as a lipotropic: i.e., a substance that improves liver function. Betaine also helps maintain intercellular osmolarity and protects proteins from becoming denatured. (1) Food sources of betaine include beets liver, eggs, fish, legumes, and whole grains. Betaine HCl is also commonly used as a nutritional supplement to increase gastric acidity. The betaine in this compound does not alter gastric acidity, but simply "delivers" the hydrochloric acid.

Biochemistry

Betaine is produced in the body by oxidation of choline, another trimethylated, methyl-donating compound. Betaine's methyl donation appears to be limited to one biochemical reaction--the conversion of homocysteine to methionine. After donating its methyl group, betaine becomes dimethylglycine (DMG). In the methionine-homocysteine cycle, the sulfur-containing essential amino acid methionine is converted to S-adenosylmethionine (SAMe), the primary methyl donor for numerous biochemical reactions in the liver and throughout human tissue. Upon losing its methyl group, SAMe becomes S-adenosylhomocysteine, which loses its adenosine, becoming homocysteine. Homocysteine is either metabolized to the amino acids cysteine and taurine (trans-sulfuration) or recycled to methionine by taking on a methyl group (methylation). This methyl group is added to homocysteine via one of two pathways. Either methylcobalamin (vitamin B12) donates a methyl group in a reaction catalyzed by the enzyme methionine synthase, or betaine donates a methyl group to homocysteine via the enzyme betaine-homocysteine methyltransferase (BHMT), a zinc-dependent metalloenzyme (Figure 1). (2,4)

[FIGURE 1 OMITTED]

Pharmacokinetics

Supplemental betaine is rapidly absorbed and distributed throughout the body, with peak concentrations being reached in less than one hour. The elimination half-life in an open-label study of 12 men was 14 hours after a single dose, and increased to 41 hours after repeated dosing for five days. Plasma DMG concentrations also increased significantly after betaine dosing, Due to extensive metabolism of the compound, only four percent of the ingested dose of betaine was eliminated via the kidneys. (1)

Mechanisms of Action

Betaine transfers its methyl group to homocysteine via the enzyme BHMT. It does not appear to be involved in any other methylation reactions.

Deficiency States

Since betaine is derived from dietary betaine, as well as via conversion from choline, a deficiency has not been documented. Certain situations, however, place an increased burden on the betaine-facilitated recycling of homocysteine, including a dietary deficiency of folic acid, alcoholism, or a genetic polymorphism involving the methylene tetrahydrofolate reductase (MTHFR) gene (which can severely decrease the activity of this enzyme). (2) In this instance, folic acid (as tetrahydrofolate) cannot be converted to 5-methyltetrahydrofolate (5-MTHF) as efficiently. As the active form of folic acid, 5-MTHF transfers its methyl group to cobalamin (vitamin B12), which in turn donates this methyl group to homocysteine in a reaction catalyzed by methionine synthase, in the case of dietary folate deficiency or MTHFR-enzyme inhibition, the betaine pathway is stressed. (2) With chronic alcohol intake, the activity of methionine synthase is inhibited; however, ill this instance BHMT activity is up-regulated in an attempt to make up for the decreased activity of the other enzyme. (5) It is unknown if BHMT activity is up-regulated in the former instances. When the activity of BHMT is increased, there is a greater need for betaine, and a conditional deficiency might result if not enough is ingested in the diet or converted from choline.

Clinical Indications

Hyperhomocysteinemia/ Homocystinuria

Many disease processes have been positively correlated with high homocysteine levels, including coronary artery disease, peripheral vascular disease, osteoporosis, rheumatoid arthritis, depression, neural tube defects, spontaneous abortion, age-related cognitive decline, vascular dementia, and Alzheimer's disease. (2,3) A high level of homocysteine is believed to be a causative factor in these diseases, although the mechanism has not been completely elucidated in every disease listed. In cases where there is a dietary, metabolic, or genetic defect in homocysteine recycling involving folic acid or methionine synthase, an adequate amount of betaine is necessary to support this process.

In individuals with homocystinuria caused by a genetic defect in cystathione beta-synthase (an enzyme in the trans-sulfuration pathway of homocysteine metabolism), characterized by very high plasma levels of homocysteine (>50 [micro]mol/ L), betaine supplementation caused a drop in homocysteine levels of up to 75 percent.(6,7)

Betaine dosing of 6 g daily significantly reduced plasma homocysteine in a placebo-controlled study of obese individuals with normal levels at baseline. (8) In an open trial of 15 healthy volunteers, homocysteine levels were significantly decreased after three weeks of betaine supplementation (6 g daily). (9)