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Methionine

Nutrient Name: Methionine.
Synonyms:DL-Methionine,L-methionine.
Related Substance: S-adenosylmethionine (SAM, SAMe; AdoMet).

Summary Table
nutrient description

Chemistry and Forms

DL-Methionine,L-methionine.

Physiology and Function

Methionine is an essential sulfur-containing amino acid that facilitates and helps initiate the translation of messenger RNA (mRNA) by being the first amino acid incorporated into the N-terminal position of all proteins. The terminal methyl group of the methionine side chain often participates in biochemical methyl transfer reactions, making methionine a member of the “methyl donor” class of biochemicals.

S-adenosylmethionine (SAMe) is intimately involved in the synthesis of brain chemicals and also in detoxification reactions. Methionine is converted into SAMe, which is considered to be the activated form of methionine. This occurs in the first step of the metabolism of methionine, which requires energy in the form of adenosine triphosphate (ATP). In this activation of methionine, an adenosyl moiety is transferred from the ATP molecule. SAMe is one of the most potent methyl donors and is involved in many methylation reactions. Its methyl group, which is attached in a sulfonium linkage with high-energy characteristics, may be donated to any of a large number of methyl-group acceptors in the presence of the appropriate enzyme. DNA methylation influences the expression of many genes and depends on the availability of methyl groups from SAMe. SAMe is intimately involved in the synthesis of neurotransmitters and also in detoxification reactions.

Along with inositol, choline (tetramethylglycine), and betaine (trimethylglycine), methionine is considered a member of the group of compounds called lipotropics that are closely involved in lipid metabolism. Transmethylation metabolic pathways closely interconnect choline, methionine, methyltetrahydrofolate (methyl-THF), and vitamins B6and B12. Methionine can be formed from homocysteine using methyl groups from methyl-THF, or using methyl groups from betaine that are derived from choline. Through interrelated pathways, methyl-THF can be formed from one-carbon units derived from serine or from the methyl groups of choline via dimethylglycine, and choline can be synthesized de novo using methyl groups derived from methionine (via SAMe).

Methionine regulates several sulfur-containing compounds in the body that play an important role in liver detoxification processes and the synthesis of structural proteins and enzymes. It acts as a sulfur donor and, as such, is the source of sulfur for biosynthesis of cysteine. Methionine is also the precursor for the synthesis of cystine and taurine and is one of three amino acids required for the synthesis of creatine. Methionine may serve as a precursor for the synthesis of glutathione, which is the substrate for glutathione peroxidase, a crucial antioxidant enzyme. Methionine assists in the metabolism of homocysteine and helps reduce histamine levels.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Methionine is an essential amino acid which is primarily administered to enhance liver functions such as detoxification and lipid metabolism and to support the function of the central nervous system (CNS) and neurotransmitters. In nutritional therapeutics, methionine can be used to increase levels of SAMe, reduced glutathione (GSH), taurine, and N-acetylcysteine (NAC) and to promote detoxification of xenobiotics via the sulfation pathway.

Historical/Ethnomedicine Precedent

Not used historically as an isolated nutrient.

Possible Uses

Acrodermatitis enteropathica, AIDS-related dementia, AIDS-related nervous system degeneration, fat maldigestion, human immunodeficiency virus (HIV) support, liver detoxification, migraine headaches, pain control, pancreatitis, Parkinson’s disease, radiation effects, schizophrenia, urinary tract infections, weight loss, Wilson’s disease.

Deficiency Symptoms

Typical symptoms associated with methionine deficiency include hair loss, hepatic dysfunction, poor skin tone, and toxic elevation of metabolic waste products.

Methionine deficiency is usually related to overall protein malnutrition. Individuals with acquired immunodeficiency syndrome (AIDS) demonstrate low levels of methionine. Experimentally, a methionine deficiency causes premature atherosclerosis in monkeys, especially if they are also deficient in vitamin B6. Methionine deficiency can also cause a folate deficiency since a deficiency causes 5-methyl-THF to accumulate in the liver. Lower methionine intake during pregnancy has been associated with neural tube defects in newborns.

Dietary Sources

Dairy products, fish, and meat (beef, chicken, pork, liver) are considered the richest dietary sources of methionine. Sunflower seeds, pumpkin seeds, sesame seeds, and lentils are also good sources of methionine. Egg yolks are particularly high in sulfur. Methionine and cysteine make up 91% of the sulfur in the yolk. Endogenous gut flora may be able to synthesize significant amounts. Homocysteine in the diet can eliminate the requirement for methionine.

Soybeans are a poor source, and soy-based infant formulas are generally low in methionine.

Dosage Forms Available

Capsule, powder, tablet; oral and intravenous (IV) administration.

Source Materials for Nutrient Preparations

MostL-methionine in supplements is produced by bacterial fermentation processes in a growth medium, from which the amino acid is then purified. Methionine used in supplements is frequently of theDLform, which implies chemical synthesis, thus resulting in a racemic mixture.

Dosage Range

Adult

  • Dietary:   No reference (recommended) daily intake (RDI) has been established. Average intake in the United States is 2.7 to 5 g per day.
  • Supplemental/Maintenance:   Dietary sources of methionine are usually adequate so supplemental methionine is usually not considered necessary. Optimal levels of intake have not been established but probably are 800 to 1000 mg daily, depending on weight, diet, and related factors.
  • Pharmacological/Therapeutic:   500 to 3000 mg per day.
  • Toxic:   No toxic dose level has been reported.

Pediatric (<18 Years)

  • Dietary:   No minimal dietary requirement established.
  • Supplemental/Maintenance:   Not currently recommended for children.
  • Pharmacological/Therapeutic:   Specific treatment recommendations have not established.
  • Toxic:   No toxic dosage level established specifically for infants and children.

Laboratory Values

Serum or Plasma Methionine

Range of normal levels for plasma methionine:

  • Children: 13 to 30 µmol/L
  • Adults: 16 to 30 µmol/L

safety profile

Overview

Methionine is usually tolerated well by most adults and generally considered to be free of adverse effects for most individuals at common dosage levels (e.g., 1-3 g/day). Toxicity is rare but possible with excessive dosage. Diets high in methionine may be associated with an increased occurrence of atherosclerosis, especially with concurrent deficiencies of vitamin B6, vitamin B12, and folic acid, resulting from elevations of blood homocysteine levels.

Nutrient Adverse Effects

General Adverse Effects

Nausea and gastrointestinal (GI) irritation are the primary signs of methionine toxicity, although occurrence is rare. Some sensitive individuals may experience gas, bloating, and digestive discomfort at levels as low as 500 mg per day. Other symptoms reportedly associated with methionine toxicity may include anorexia, ataxia, hyperactivity, reduced growth, hemosiderosis, and suppressed hematocrit. Extremely high doses may increase urinary calcium excretion and could potentially induce hallucinations. However, administration of up to 2 g daily for extended periods has not been associated with any serious adverse effects.

Rats fed methionine as 50% of dietary protein (equivalent human dose of 25 g/day) exhibited hyperactivity, anorexia, reduced growth, and iron accumulation in the spleen.

Pregnancy and Nursing

Evidence is lacking within the scientific literature to suggest or confirm any adverse effects related to fetal development during pregnancy or to infants who are breast-fed associated with methionine administration. Caution still advised.

Infants and Children

No adverse effects have been reported. However, sufficient research-based evidence is lacking to guarantee the safety of methionine in infants and children.

Contraindications

Avoid S-adenosylmethionine (SAMe) in Parkinson’s disease; administration may aggravate symptoms caused by serotonergic effect.

Precautions and Warnings

Large intakes of methionine require higher intakes of methyl donor–related nutrients, such as B12, folic acid, pyridoxine, choline (tetramethylglycine), betaine (trimethylglycine), and dimethylglycine. Large loads of dietary methionine without concomitant intake of these interdependent nutrients at adequate levels can increase the conversion of methionine to homocysteine (Hcy) and will result in higher levels of Hcy, a vasculotoxic product of intermediary metabolism. Need for methyl donor nutrients in relation to methionine intake varies according to pharmacogenomic determinants, such as methyl-THF reductase enzyme activity. In cases of strong family history of coronary heart disease, it would be judicious to check Hcy levels before and during methionine treatment, because of the potential homocysteinergic and atherogenic effects of methionine.

Animal research conducted by Toborek and Hennig 1 suggests that high dietary intake of methionine, in the presence of B-vitamin deficiencies, may increase the risk for atherosclerosis by increasing blood levels of cholesterol and Hcy. Troen et al. 2 observed that apolipoprotein E–deficient mice fed methionine-rich diets developed significant atheromatous pathology in the aortic arch, even with normal plasma Hcy levels. These findings suggest that moderate increases in methionine intake are atherogenic in susceptible mice.

Administration may be inappropriate in individuals with osteoporosis because high dosage levels increase urinary excretion of calcium.

interactions review

Strategic Considerations

The issue of methionine function and exogenous administration in individuals with Parkinson’s disease and related degenerative neurotransmitter conditions remains unclear, inconclusive, and contentious. Preliminary research by Smythies and Halsey suggests that methionine (5 g/day) may help ameliorate some symptoms of Parkinson’s disease. However, some authors have suggested that exogenous methionine, as with other amino acids, may interfere with the absorption or action of the levodopa, particularly in the treatment of individuals with Parkinson’s disease. Several studies have reported elevated plasma levels of total Hcy, along with decreased methionine and SAMe, in patients treated long term with levodopa and dopa decarboxylase inhibitors (DDIs) as a result of alterations in levels of substrates of the O-methylation cycle. 3

Several studies have investigated the use of methionine coadministration as a means of reducing toxicity caused by acetaminophen and suggested the probable benefits of such an integrative approach to prescribing.

Viewing methionine administration or supplementation within the larger context of wellness and therapeutics, it is important to note that increasing intake of methionine without providing for adequate intake of folic acid, vitamin B6, and vitamin B12can augment the conversion of methionine to Hcy and thereby increase cardiovascular risk.

nutrient-drug interactions
Acetaminophen
Acetaminophen (APAP, paracetamol; Tylenol); combination drugs: acetaminophen and codeine (Capital and Codeine; Phenaphen with Codeine; Tylenol with Codeine); acetaminophen and hydrocodone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); acetaminophen and oxycodone (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen and pentazocine (Talacen); acetaminophen and propoxyphene (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic); acetaminophen, butalbital, and caffeine (Fioricet).
Prevention or Reduction of Drug Adverse Effect
Beneficial or Supportive Interaction, Not Requiring Professional Management

Probability: 2. Probable to 1. Certain
Evidence Base: Emerging

Effect and Mechanism of Action

Methionine appears to reduce the toxic effects of acetaminophen (paracetamol), particularly on the liver, without adversely affecting (and possibly enhancing) the drug’s pharmacokinetics and efficacy. Glutathione is most likely central to such activity, but the mechanisms involved have yet to be fully elucidated. The observed phenomenon might relate to empirical reports of methionine use in liver detoxification; however, the available evidence is not sufficient to support such an extrapolation. Further research is warranted to investigate the mechanisms of action responsible for the observed effects.

Research

Acetaminophen (paracetamol) poisoning is a major source of morbidity and mortality and represents one of the most common examples of adverse drug reactions in conventional medical practice. Numerous studies have demonstrated that coadministration of methionine may be effective in the treatment of acetaminophen toxicity. For more than a decade, various researchers and clinicians have proposed that methionine be incorporated into acetaminophen tablets routinely as a protective mechanism against acetaminophen-induced toxicity.

Skoglund and Skjelbred 4 conducted a randomized, single-blind, between-patient study comparing the onset of analgesia, duration, and efficacy of paracetamol versus a combination medication containing free paracetamol and its N-acetylmethionate ester (SUR 2647) in outpatients after oral surgery. Using several subjective and objective assessments, the authors reported that median onset of analgesia for both groups was approximately equivalent (i.e., ≤½ hour) and that the duration of analgesia after the combination was greater than that for paracetamol (i.e., ≥5.5 hours vs. ≥2.5 hours). Furthermore, the combination regimen reduced pain significantly more than the paracetamol from ½ to 3 hours after initiation of medication, but the mean pain scores did not show a significant difference during the remaining observation period. Subjects in both treatment groups reported mild to moderate drowsiness, but it was more common in subjects given the paracetamol/methionine combination.

Research by Neuvonen et al. 5 indicates that methionine might protect against the hepatotoxic effects of acetaminophen. Using a rat model, they compared the analgesic effect, toxicity, and kinetics of oral paracetamol with those of paracetamol+ L-methionine (5:1). They reported that the presence of methionine did not significantly change the analgesic effect of paracetamol, but that methionine reduced the acute toxicity (LD 50 ) of paracetamol by 50% in nonfasted, fasted, and phenobarbital-pretreated mice. Subsequently, in a small, randomized crossover study involving 10 human subjects, they observed that coadministration of methionine (300 mg) did not alter the pharmacokinetics of paracetamol (1500 mg). Furthermore, they found that the “absorption of methionine from the combination tablets was rapid, peak concentrations occurred in plasma at 30 min and were 3-4 times higher than after paracetamol tablets not containing methionine.” 5 In a later paper, some of these same researchers reviewed their findings and related data and rhetorically asked, “Why not add methionine to paracetamol tablets?” 6

Based on these concerns and the emerging pattern of evidence supporting coadministration of methionine with acetaminophen, McAuley et al. 7 investigated whether methionine administration might adversely affect cardiovascular risk factors through its effect on endothelial function, plasma homocysteine (Hcy), and lipid peroxidation in 16 healthy volunteers. Their findings showed no significant difference in endothelial-dependent vascular responses after acute (250 mg orally), 1 month of low-dose (250 mg daily), or 1 week of high-dose (100 mg/kg daily) methionine. Plasma Hcy concentrations demonstrated no significant differences after acute or 1 month of low-dose methionine. However, Hcy concentrations significantly increased after 1 week of high-dose methionine (100 mg/kg) daily. Thus, methionine administration at dosage levels similar to those used in combination preparations with acetaminophen do not adversely affect plasma Hcy concentrations. The observation that high-dose methionine administration can cause elevated plasma Hcy concentrations in only 1 week is consistent with other research findings on methionine administration outside the context of synergistic nutrients.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Pending release of a commercial product combining acetaminophen and methionine, health care professionals are advised that it is reasonable to coadminister the two agents, particularly for patients who take acetaminophen on a long-term basis, such as for osteoarthritis. Although definitive conclusions from large, well-designed, controlled, double-blind clinical trials is lacking at this time, the evidence thus far available strongly indicates a pattern of clinical efficacy and lack of adverse effects associated with such coordinated use. Monitoring of Hcy would be judicious with long-term use in at-risk patients.

Levodopa
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Vidarabine
nutrient-nutrient interactions
Antioxidants
Folate, Vitamin B 6 , and Vitamin B 12
Citations and Reference Literature
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