L-Methionine modulates mTOR signaling through amino acid sensing mechanisms [2]; activates heme oxygenase-1 (HO-1) and ferritin expression[3]; induces Nrf2-ARE antioxidant pathway[5]; regulates DNA methylation via DNMT enzymes in hippocampal neurons[4]

In human pancreatic cancer cells (PANC-1 and MIA PaCa-2), L-Methionine (10 mM) inhibited proliferation by 45-52% at 72h (MTT assay), induced G0/G1 cell cycle arrest (flow cytometry: G0/G1 fraction increased from 58% to 78%), and increased apoptosis (Annexin V-positive cells rose from 8% to 32%) [1]

In mouse mammary epithelial cells (HC11), L-Methionine (0.6 mM) stimulated mTOR phosphorylation and increased β-casein expression 2.5-fold; ARID1B overexpression blocked these effects and reduced proliferation by 40% (p<0.01) [2]

In HUVECs, pretreatment with L-Methionine (5 mM, 24h) upregulated HO-1 protein 3.2-fold (western blot), increased ferritin 2.1-fold, and reduced H₂O₂-induced ROS by 65% (DCFDA assay, p<0.001) while enhancing nitric oxide production 80% (Griess assay) [3].

In aged rats (24 months), intraperitoneal L-Methionine (100 mg/kg/day ×14 days) improved Morris water maze performance (escape latency ↓35%, p<0.01), upregulated hippocampal BDNF (+42%) and synapsin-1 (+38%), and increased global DNA methylation 25% (ELISA) [4]

In high-fat diet-fed rats, dietary L-Methionine (0.5% w/w ×8 weeks) decreased hepatic ROS 50%, increased Nrf2 nuclear translocation 2.3-fold, and upregulated antioxidant enzymes: SOD↑75%, GPx↑62%, CAT↑58% (p<0.001) [5]

Cognitive studies: Aged SD rats received daily IP injections of L-Methionine (100 mg/kg in saline) for 14 days. Behavioral tests conducted on days 7-14; brains harvested 24h post-final dose [4]

Oxidative stress studies: Weanling rats fed high-fat diets (45% kcal fat) supplemented with 0.5% (w/w) L-Methionine for 8 weeks. Liver/plasma collected after overnight fasting [5]

Absorption, Distribution and Excretion
Absorbed from the lumen of the small intestine into the enterocytes by an active transport process.
... Rats were fed diets containing [(14)C-methyl]l-methionine ... with 6% of sodium formate, and conversion of (14)C into [(14)C]formate was measured in urine and exhaled air (as (14)CO2) ... Total oxidation of [(14)C-methyl] into CO2, amounted to 60-87% for methionine ...
Although the free amino acids dissolved in the body fluids are only a very small proportion of the body's total mass of amino acids, they are very important for the nutritional and metabolic control of the body's proteins. ... Although the plasma compartment is most easily sampled, the concentration of most amino acids is higher in tissue intracellular pools. Typically, large neutral amino acids, such as leucine and phenylalanine, are essentially in equilibrium with the plasma. Others, notably glutamine, glutamic acid, and glycine, are 10- to 50-fold more concentrated in the intracellular pool. Dietary variations or pathological conditions can result in substantial changes in the concentrations of the individual free amino acids in both the plasma and tissue pools. /Amino acids/
After ingestion, proteins are denatured by the acid in the stomach, where they are also cleaved into smaller peptides by the enzyme pepsin, which is activated by the increase in stomach acidity that occurs on feeding. The proteins and peptides then pass into the small intestine, where the peptide bonds are hydrolyzed by a variety of enzymes. These bond-specific enzymes originate in the pancreas and include trypsin, chymotrypsins, elastase, and carboxypeptidases. The resultant mixture of free amino acids and small peptides is then transported into the mucosal cells by a number of carrier systems for specific amino acids and for di- and tri-peptides, each specific for a limited range of peptide substrates. After intracellular hydrolysis of the absorbed peptides, the free amino acids are then secreted into the portal blood by other specific carrier systems in the mucosal cell or are further metabolized within the cell itself. Absorbed amino acids pass into the liver, where a portion of the amino acids are taken up and used; the remainder pass through into the systemic circulation and are utilized by the peripheral tissues. /Amino acids/
Protein secretion into the intestine continues even under conditions of protein-free feeding, and fecal nitrogen losses (ie, nitrogen lost as bacteria in the feces) may account for 25% of the obligatory loss of nitrogen. Under this dietary circumstance, the amino acids secreted into the intestine as components of proteolytic enzymes and from sloughed mucosal cells are the only sources of amino acids for the maintenance of the intestinal bacterial biomass. ... Other routes of loss of intact amino acids are via the urine and through skin and hair loss. These losses are small by comparison with those described above, but nonetheless may have a significant impact on estimates of requirements, especially in disease states. /Amino acids/
For more Absorption, Distribution and Excretion (Complete) data for (L)-Methionine (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hepatic
Product of oxidative deamination or transamination--alpha-keto-gamma-methiolbutyric acid. /From table/
... Oxidation of methionine (S-methyl-l-cysteine and sarcosine) methyl group in vivo proceeds primarily by way of free formate, and that conversion to formate is probably not catalysed by tetrahydrofolic acid.
... Methionine ... is catabolized to a large extent independently of initial activation to S-adenosyl-l-methionine. The system for catabolism ... appears analogous to one that catalyses oxidation of S-methyl-l-cysteine methyl group ... The methyl group of methionine ... /has been/ shown ... to yield formate in vitro and in vivo.
Infants more rapidly metabolized methionine than adults.
For more Metabolism/Metabolites (Complete) data for (L)-Methionine (7 total), please visit the HSDB record page.
Hepatic

Toxicity Summary
The mechanism of the possible anti-hepatotoxic activity of L-methionine is not entirely clear. It is thought that metabolism of high doses of acetaminophen in the liver lead to decreased levels of hepatic glutathione and increased oxidative stress. L-methionine is a precursor to L-cysteine. L-cysteine itself may have antioxidant activity. L-cysteine is also a precursor to the antioxidant glutathione. Antioxidant activity of L-methionine and metabolites of L-methionine appear to account for its possible anti-hepatotoxic activity. Recent research suggests that methionine itself has free-radical scavenging activity by virtue of its sulfur, as well as its chelating ability.

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Interactions
The adverse effects of methionine are alleviated by supplements of glycine or serine ... Vit B6 deficiency reduces the tolerance of the rat for methionine.
Pretreatment of young male rats with excess retinol (800 IU/g diet for 10 days) partially counteracted the adverse effects caused by a high methionine intake.
Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approx twice the level of serum free methionine and consumed only one half the volume of water as controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from the teratogenic effects of sodium valproate ... Protection from the teratogenic effects of sodium valproate was afforded by methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine.
This study showed that short-term vitamin administration /(folic acid, vitamins B6 and B12)/ effectively reduced post-methionine load homocysteine levels and thereby ameliorated endothelium-dependent flow-mediated vasodilation in 16 healthy adults. Post-methionine load homocysteine levels decreased from 22.7+/-3.8 to 17.0+/-2.1 micromol/L (p <0.001), and flow-mediated vasodilation after methionine load increased from 8.6+/-3.6% to 13.8+/-2.9% (p <0.001) after vitamin administration.
For more Interactions (Complete) data for (L)-Methionine (18 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 36,000 mg/kg
LD50 Rat ip 4238 mg/kg

[1]. L-Methionine inhibits growth of human pancreatic cancer cells. Anticancer Drugs. 2014 Feb;25(2):200-3. [2]. ARID1B blocks methionine-stimulated mTOR activation to inhibit milk fat and protein synthesis in and proliferation of mouse mammary epithelial cells. J Nutr Biochem. 2023 Jan 18;114:109274. [3]. L-methionine reduces oxidant stress in endothelial cells: role of heme oxygenase-1, ferritin, and nitric oxide. AAPS J. 2005 Aug 29;7(1):E195-200. [4]. Prelimbic Cortical Stimulation with L-methionine Enhances Cognition through Hippocampal DNA Methylation and Neuroplasticity Mechanisms. Aging Dis. 2023 Feb 1;14(1):112-135. [5]. L-Methionine activates Nrf2-ARE pathway to induce endogenous antioxidant activity for depressing ROS-derived oxidative stress in growing rats. J Sci Food Agric. 2019 Aug 15;99(10):4849-4862.

Therapeutic Uses
A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals
Methionine ... enhances the synthesis of glutathione and is used as an alternative to acetylcysteine in the treatment of paracetamol poisoning.
... Many of signs of toxicity /of selenium poisoning/ can be prevented by high-protein diets, and by methionine in the presence of Vitamin E.
In Europe, oral methionine (10 g over 12 hours) is approved as an agent to restore depleted glutathione stores and prevent hepatotoxicity after large acetaminophen ingestions. N-Acetyl-L-cysteine remains the preferred antidote for acetaminophen overdose in the United States, Canada, Scotland, and most of England.
For more Therapeutic Uses (Complete) data for (L)-Methionine (9 total), please visit the HSDB record page.

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Drug Warnings
Methionine may cause nausea, vomiting, drowsiness, and irritability. It should not be used in patients with acidosis. Methionine may aggravate hepatic encephalopathy in patients with established liver damage; it should be used with caution in patients with severe liver disease.
Vomiting is a common adverse effect.
Methionine ... may exacerbate hepatic encephalopathy when administered more than 10 hours postingestion.
The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.
When studying genetic factors in arteriosclerosis /the authors/ recorded acute complications during a standard methionine loading test (with a dose of 100 mg/kg bw) and assessed a 30-day mortality in a group of 296 patients with coronary artery or peripheral arterial disease and in 591 controls. Acute complications were observed in 33% of the women and 16.5% of the men. For each sex, the patients and controls exhibited the same proportion of complications. The most common symptom, dizziness, was attributable to methionine loading. In addition, isolated sleepiness, nausea, polyuria and decreased or increased blood pressure were observed in part of the subjects. None of the 887 individuals died within the 30-day period following the test...

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Pharmacodynamics
L-Methionine is a principle supplier of sulfur which prevents disorders of the hair, skin and nails; helps lower cholesterol levels by increasing the liver's production of lecithin; reduces liver fat and protects the kidneys; a natural chelating agent for heavy metals; regulates the formation of ammonia and creates ammonia-free urine which reduces bladder irritation; influences hair follicles and promotes hair growth. L-methionine may protect against the toxic effects of hepatotoxins, such as acetaminophen. Methionine may have antioxidant activity.

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A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals.
L-Methionine is a metabolite found in or produced by Escherichia coli (strain K12, MG1655).
Methionine has been reported in Pinus densiflora, Cyperus aromaticus, and other organisms with data available.
Methionine is one of nine essential amino acids in humans (provided by food), Methionine is required for growth and tissue repair. A sulphur-containing amino acid, methionine improves the tone and pliability of skin, hair, and strengthens nails. Involved in many detoxifying processes, sulphur provided by methionine protects cells from pollutants, slows cell aging, and is essential for absorption and bio-availability of selenium and zinc. Methionine chelates heavy metals, such as lead and mercury, aiding their excretion. It also acts as a lipotropic agent and prevents excess fat buildup in the liver. (NCI04)

METHIONINE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) and has 12 investigational indications.
Methionine is a dietary indispensable amino acid required for normal growth and development of humans, other mammals, and avian species. In addition to being a substrate for protein synthesis, it is an intermediate in transmethylation reactions, serving as the major methyl group donor in vivo, including the methyl groups for DNA and RNA intermediates. Methionine is a methyl acceptor for 5-methyltetrahydrofolate-homocysteine methyl transferase (methionine synthase), the only reaction that allows for the recycling of this form of folate, and is also a methyl acceptor for the catabolism of betaine. Methionine is also required for synthesis of cysteine. Methionine is accepted as the metabolic precursor for cysteine. Only the sulfur atom from methionine is transferred to cysteine; the carbon skeleton of cysteine is donated by serine. The adequacy range of dietary requirements of specific amino acids in disease states is difficult to determine. Requirements may not be similar in disease with regard to protein synthesis. Requirements for this purpose can be assessed only when such a function can be measured and related to clinical outcome. There is apparent consensus concerning normal sulfur amino acid (SAA) requirements. WHO recommendations amount to 13 mg/kg per 24 h in healthy adults. This amount is roughly doubled in artificial nutrition regimens. In disease or after trauma, requirements may be altered for methionine, cysteine, and taurine. Although in specific cases of congenital enzyme deficiency, prematurity, or diminished liver function, hypermethionemia or hyperhomocysteinemia may occur, SAA supplementation can be considered safe in amounts exceeding 2-3 times the minimal recommended daily intake. Apart from some very specific indications (e.g., acetaminophen poisoning) the usefulness of SAA supplementation is not yet established. Methionine is known to exacerbate psychopathological symptoms in schizophrenic patients, there is no evidence of similar effects in healthy subjects. The role of methionine as a precursor of homocysteine is the most notable cause for concern. A loading dose of methionine (0.1 g/kg) has been given, and the resultant acute increase in plasma homocysteine has been used as an index of the susceptibility to cardiovascular disease. Although this procedure results in vascular dysfunction, this is acute and unlikely to result in permanent damage. However, a 10-fold larger dose, given mistakenly, resulted in death. Longer-term studies in adults have indicated no adverse consequences of moderate fluctuations in dietary methionine intake, but intakes higher than 5 times normal resulted in elevated homocysteine levels. These effects of methionine on homocysteine and vascular function are moderated by supplements of vitamins B-6, B-12, C, and folic acid. In infants, methionine intakes of 2 to 5 times normal resulted in impaired growth and extremely high plasma methionine levels, but no adverse long-term consequences were observed.
A sulfur-containing essential L-amino acid that is important in many body functions.

C5H11NO2S

149.2

149.051

C, 40.25; H, 7.43; N, 9.39; O, 21.45; S, 21.49

63-68-3

26062-47-5

6137

Minute hexagonal plates from dilute alcohol
Colorless or white, lustrous plates or as white, crystalline powder

1.2±0.1 g/cm3

306.9±37.0 °C at 760 mmHg

284 °C (dec.)(lit.)

139.4±26.5 °C

0.0±1.4 mmHg at 25°C

1.531

0.37

2

4

4

9

97

1

S(C([H])([H])[H])C([H])([H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])[H]

FFEARJCKVFRZRR-BYPYZUCNSA-N

InChI=1S/C5H11NO2S/c1-9-3-2-4(6)5(7)8/h4H,2-3,6H2,1H3,(H,7,8)/t4-/m0/s1

(2S)-2-amino-4-methylsulfanylbutanoic acid

Methionine; L-Methionine; MET; NSC-22946; 63-68-3; methionine; h-Met-oh; Cymethion; S-Methionine; Neo-methidin; Methilanin; NSC22946; NSC 22946

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~16.67 mg/mL (~111.72 mM)

Solubility in Formulation 1: 12.5 mg/mL (83.77 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)