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Betaine Monograph Monograph Betaine H O CH3 C C N CH3 HO H CH3 Betaine Betaine Introduction Betaine (trimethylglycine), the trimethylated com- pound of the amino acid glycine, is an essential biochemi- cal component of the methionine/homocysteine cycle. Be- taine acts as a donor of methyl (CH3) 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 acid- ity, 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 (methyla- tion). This methyl group is added to homocysteine via one of two pathways. Either methylcobalamin (vita- min B12) donates a me- thyl group in a reaction catalyzed by the enzyme methionine synthase, or Figure 1. Involvement of Betaine in Homocysteine Recycling betaine donates a methyl group to homocysteine Homocysteine via the enzyme betaine- THF Methyl B12 homocysteine SAMe Betaine/BHMT methyltransferase MS (BHMT), a zinc-depen- dent metalloenzyme 5MTHF B12 Methionine (Figure 1).2-4 THF - tetrahydrofolate 5MTHF - 5-methyl tetrahydrofolate MS - methionine synthase SAMe - S-adenosylmethionine BHMT - betaine-homocysteine methyltransferase Alternative Medicine Review ◆ Volume 8, Number 2 ◆ 2003 Page 193 Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Betaine Monograph Pharmacokinetics Clinical Indications Supplemental betaine is rapidly absorbed Hyperhomocysteinemia/ and distributed throughout the body, with peak con- Homocystinuria centrations being reached in less than one hour. The elimination half-life in an open-label study of 12 men Many disease processes have been posi- was 14 hours after a single dose, and increased to 41 tively correlated with high homocysteine levels, hours after repeated dosing for five days. Plasma including coronary artery disease, peripheral vas- DMG concentrations also increased significantly cular disease, osteoporosis, rheumatoid arthritis, after betaine dosing. Due to extensive metabolism depression, neural tube defects, spontaneous abor- tion, age-related cognitive decline, vascular de- of the compound, only four percent of the ingested 2,3 dose of betaine was eliminated via the kidneys.1 mentia, and Alzheimer’s disease. A high level of homocysteine is believed to be a causative fac- tor in these diseases, although the mechanism has Mechanisms of Action not been completely elucidated in every disease Betaine transfers its methyl group to ho- listed. In cases where there is a dietary, metabolic, mocysteine via the enzyme BHMT. It does not ap- or genetic defect in homocysteine recycling in- pear to be involved in any other methylation reac- volving folic acid or methionine synthase, an ad- tions. equate amount of betaine is necessary to support this process. Deficiency States In individuals with homocystinuria caused Since betaine is derived from dietary be- by a genetic defect in cystathione beta-synthase taine, as well as via conversion from choline, a (an enzyme in the trans-sulfuration pathway of ho- deficiency has not been documented. Certain situ- mocysteine metabolism), characterized by very ations, however, place an increased burden on the high plasma levels of homocysteine (>50 µmol/ betaine-facilitated recycling of homocysteine, in- L), betaine supplementation caused a drop in ho- cluding a dietary deficiency of folic acid, alco- mocysteine levels of up to 75 percent.6,7 holism, or a genetic polymorphism involving the Betaine dosing of 6 g daily significantly methylene tetrahydrofolate reductase (MTHFR) reduced plasma homocysteine in a placebo-con- gene (which can severely decrease the activity of trolled study of obese individuals with normal lev- this enzyme).2 In this instance, folic acid (as els at baseline.8 In an open trial of 15 healthy vol- tetrahydrofolate) cannot be converted to 5- unteers, homocysteine levels were significantly methyltetrahydrofolate (5-MTHF) as efficiently. decreased after three weeks of betaine supplemen- As the active form of folic acid, 5-MTHF trans- tation (6 g daily).9 fers its methyl group to cobalamin (vitamin B12), which in turn donates this methyl group to ho- Cardiovascular Diseases mocysteine in a reaction catalyzed by methionine High levels of homocysteine have been synthase. In the case of dietary folate deficiency linked to increased risk of coronary artery dis- or MTHFR-enzyme inhibition, the betaine path- 10,11 12-14 ease, myocardial infarction, cerebral occlu- 2 way is stressed. With chronic alcohol intake, the sive disease,15,16 and peripheral occlusive disease activity of methionine synthase is inhibited; how- (i.e., deep vein thrombosis; intermittent claudica- ever, in this instance BHMT activity is up-regu- tion).17 Homocysteine-lowering interventions us- lated in an attempt to make up for the decreased ing nutritional cofactors have been shown to re- 5 activity of the other enzyme. It is unknown if duce the risk of cardiovascular events.18-20 These BHMT activity is up-regulated in the former in- interventions have mainly included supplementa- stances. When the activity of BHMT is increased, tion of folic acid, vitamin B12, and vitamin B6. there is a greater need for betaine, and a condi- In the few studies that have been conducted uti- tional deficiency might result if not enough is in- lizing betaine, 6 g has been the standard dose gested in the diet or converted from choline. shown to be effective in lowering homocysteine Page 194 Alternative Medicine Review ◆ Volume 8, Number 2 ◆ 2003 Copyright©2003 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission Monograph Betaine levels and cardiovascular risk in individuals who Alcohol-Induced Liver Disease 20-22 did not respond to B6, B12, and folate. No stud- The activity of the enzyme methionine ies have supplemented betaine alone. synthase is severely inhibited by chronic alcohol ingestion; however, alcohol causes BHMT activ- Non-Alcoholic Fatty Liver Disease ity to be up-regulated.5 This is an occasion when (NAFLD; Fatty Liver) betaine supplementation might be helpful, al- NAFLD comprises a broad spectrum though no human clinical studies have been con- ranging from simple hepatic steatosis (fatty liver) ducted to date. In rats dosed chronically with al- to non-alcoholic steatohepatitis (NASH), which cohol, then given betaine, hepatic steatosis was 27 can lead to fibrosis, cirrhosis, and liver failure. ameliorated. Supplemental betaine has been The average incidence of NAFLD in the U.S. shown to increase the production of the vital me- population is 20 percent, although it is usually thyl donor SAMe, which is depleted in alcohol- 28 asymptomatic. NASH is the most common form ism. of progressive liver disease in the United States, affecting three percent of the population. Of those Obesity people with NASH, 50 percent progress to fibro- Since betaine has a positive effect on fat sis, 15-30 percent to cirrhosis, and three percent metabolism in the liver, and decreases adipose tis- to liver failure. It is thought that the liver damage sue in pigs, it has been postulated that betaine in NASH is a consequence of insulin resistance might decrease fat mass in humans. Schwab et al and/or obesity, which results in increased hepatic gave 42 obese people 6 g betaine daily or placebo fat synthesis, increased triglycerides in hepato- for 12 weeks and found no significant difference cytes, and oxidative stress-induced hepatocellu- in body weight or composition in the two groups. lar damage. Aminotransferase liver enzymes are Homocysteine concentrations decreased signifi- often chronically elevated by 200-300 percent.23 cantly in the betaine-supplemented group.8 Betaine has been used as a lipotropic, and to prevent and treat NAFLD. Methyl groups are Side Effects and Toxicity necessary for the conversion of phosphatidyletha- Betaine is generally well tolerated, al- nolamine to phosphatidylcholine, and betaine may though nausea, loose stools, abdominal cramps, be able to act as a methyl donor in this instance. and body odor have been noted.25 Elevated blood homocysteine is seen in NASH,24 which may be a sign of decreased methyl group Dosage availability. In a small study of 10 NASH patients given 20 g betaine daily for one year, significant The standard dosage in most betaine stud- improvements in aminotransferase enzymes (ALT, ies has been 6 g/day in divided doses, although AST) were noted, with normalization of these doses as high as 20 g have been used. enzymes in three patients. Upon follow-up liver biopsy, decreases in steatosis and fibrosis were References seen.25 1. Schwahn BC, Hafner D, Hohlfeld T, et al. Pharma- In a double-blind, placebo-controlled cokinetics of oral betaine in healthy subjects and study of betaine supplementation in 191 NASH patients with homocystinuria. Br J Clin Pharmacol 2003;55:6-13. patients, after eight weeks the patients given be- 2. Miller AL, Kelly GS. Homocysteine metabolism: taine had a 25-percent decrease in hepatic steato- nutritional modulation and impact on health and sis and significant decrease in liver enzymes.26 disease.
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