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 into intestinal cells via active transport from the small intestinal lumen. ...Rats were fed a diet containing [(14)C-methyl]1-methionine...with 6% sodium formate added, and the amount of [(14)C] converted to [(14)C]formate (in the form of (14)CO2) in urine and exhaled air was measured...The proportion of [(14)C-methyl] in methionine completely oxidized to CO2 was 60-87%... Although free amino acids dissolved in body fluids constitute only a small portion of the total amino acids in the body, they are crucial for the nutritional and metabolic regulation of proteins. ...While plasma is the easiest to sample, most amino acids are found in higher concentrations in the intracellular pools of tissue cells. Typically, large neutral amino acids, such as leucine and phenylalanine, are in near-equilibrium with their plasma concentrations. Other amino acids, particularly glutamine, glutamic acid, and glycine, are 10 to 50 times higher in the intracellular pools than in plasma. Dietary changes or pathological conditions can lead to significant alterations in the concentrations of various free amino acids in plasma and tissue pools. /Amino Acids/
After ingestion, proteins denature under the influence of gastric acid and are hydrolyzed into smaller peptides by pepsin. The activity of pepsin increases with the increase in gastric acid after eating. These proteins and peptides then enter the small intestine, where peptide bonds are hydrolyzed by various enzymes. These specific peptide-hydrolyzing enzymes originate from the pancreas and include trypsin, chymotrypsin, elastase, and carboxypeptidase. The resulting mixture of free amino acids and small peptides is then transported to mucosal cells via various carrier systems, each targeting specific amino acids, dipeptides, and tripeptides, with each system targeting only a limited range of peptide substrates. After intracellular hydrolysis of the absorbed peptides, the free amino acids are subsequently secreted into the portal vein bloodstream via other specific carrier systems within the mucosal cells, or further metabolized intracellularly. The absorbed amino acids enter the liver, where some are absorbed and utilized; the remainder enters the systemic circulation and is utilized by peripheral tissues. Even under protein-free feeding conditions, protein continues to be secreted into the gut, and fecal nitrogen loss (i.e., nitrogen lost in feces as bacteria) may account for up to 25% of essential nitrogen loss. Under these dietary conditions, amino acids secreted into the gut as components of proteolytic enzymes and amino acids from shed mucosal cells are the only amino acid sources for maintaining gut bacterial biomass. …Other pathways of loss of complete amino acids include urinary excretion and shedding of skin and hair. These losses are smaller compared to the pathways mentioned above, but can still significantly affect the estimation of requirements, especially in disease states. /Amino Acids/
For more data on the absorption, distribution, and excretion (complete) of (L)-methionine (11 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Hepatic
Product of oxidative deamination or transamination—α-keto-γ-methionine butyrate. /Excerpt from Table/
...The oxidation of the methyl group of methionine (S-methyl-L-cysteine and sarcosine) in vivo mainly occurs via the free formic acid pathway, while tetrahydrofolate may not catalyze this formic acid conversion.
...Methionine...is catabolized largely independently of its initial activation to S-adenosyl-L-methionine. This catabolistic system...appears to be similar to the system that catalyzes the oxidation of the methyl group of S-methyl-L-cysteine...The methyl group of methionine...has been shown...to generate formic acid both in vitro and in vivo.
Infants metabolize methionine faster than adults.
For more complete data on the metabolism/metabolites of (L)-methionine (7 in total), please visit the HSDB record page.
Liver

Toxicity Summary
The mechanism by which L-methionine may possess hepatotoxicity resistance is not fully understood. It is believed that the metabolism of high doses of acetaminophen in the liver leads to decreased hepatic glutathione levels and increased oxidative stress. L-methionine is a precursor to L-cysteine. L-cysteine itself may possess antioxidant activity. L-cysteine is also a precursor to the antioxidant glutathione. The antioxidant activity of L-methionine and its metabolites appears to be the reason for its potential hepatotoxicity resistance. Recent studies have shown that methionine itself possesses free radical scavenging activity, thanks to its sulfur atom and chelating ability. Interactions Supplementation with glycine or serine can alleviate the adverse effects of methionine… Vitamin B6 deficiency reduces tolerance to methionine in rats. Pretreatment of juvenile male rats with excessive retinol (800 IU/g diet for 10 days) can partially offset the adverse effects caused by high methionine intake. Adding methionine to the drinking water of pregnant rats injected with sodium valproate reduced embryo reabsorption but did not improve embryonic growth. The serum free methionine level in rats drinking water supplemented with methionine was approximately twice that of the control group, while their water intake was only half that of the control group. Using whole rat embryo culture, simultaneous addition of methionine and sodium valproate to the culture medium did not protect embryos from the teratogenic effects of sodium valproate… however, methionine did protect embryos from the teratogenic effects of sodium valproate, especially when the cultured embryos were taken from pregnant rats that had ingested methionine; this protective effect was more significant. This study demonstrates that short-term vitamin supplementation (folic acid, vitamin B6, and B12) can effectively reduce homocysteine levels after methionine loading, thereby improving endothelial-dependent flow-mediated vasodilation in 16 healthy adults. Following methionine loading, homocysteine levels decreased from 22.7 ± 3.8 μmol/L to 17.0 ± 2.1 μmol/L (p < 0.001), while flow-mediated vasodilation increased from 8.6 ± 3.6% to 13.8 ± 2.9% (p < 0.001). For more complete data on interactions with (L)-methionine (18 in total), please visit the HSDB record page. Non-human toxicity values: Oral LD50 in rats: 36,000 mg/kg; Intraperitoneal LD50 in rats: 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
Methionine is a sulfur-containing essential amino acid crucial for many bodily functions. It is a heavy metal chelator. Methionine…enhances glutathione synthesis and can be used as an alternative to acetylcysteine in the treatment of acetaminophen poisoning. Many symptoms of selenium poisoning can be prevented by a high-protein diet and by taking methionine in the presence of vitamin E. In Europe, oral methionine (10 grams over 12 hours) has been approved for replenishing depleted glutathione reserves and preventing hepatotoxicity following high doses of acetaminophen. In the United States, Canada, Scotland, and most of England, N-acetyl-L-cysteine remains the antidote of choice for acetaminophen overdose. For more complete data on the therapeutic uses of (L)-methionine (9 types), please visit the HSDB records page. Drug Warnings Methionine may cause nausea, vomiting, drowsiness, and irritability. It should not be used in patients with acidosis. Methionine may exacerbate hepatic encephalopathy in patients with confirmed liver damage; caution should be exercised when using it in patients with severe liver disease. Vomiting is a common adverse reaction. Methionine…taking it more than 10 hours after ingestion may exacerbate hepatic encephalopathy. This article reports a case of death in a control subject after oral administration of a large dose of methionine. This study aimed to explore the possible relationship between homocysteine and Alzheimer's disease. The subject's plasma methionine concentration after oral administration was significantly higher than previously reported concentrations in humans taking the standard oral dose of methionine (100 mg/kg body weight). Pre-administration plasma metabolite values ruled out known genetic disorders that could cause abnormally high methionine concentrations. The most likely explanation is that the subject ingested an excessive amount of methionine. This article explores the possibility that extremely high concentrations of methionine may lead to severe brain damage and recommends against increasing the dose of methionine to improve the sensitivity of standard methionine loading tests, or if attempted, with extreme caution.
In studying the genetic factors of atherosclerosis, the authors documented acute complications during a standard methionine loading test (dose of 100 mg/kg body weight) and assessed 30-day mortality in 296 patients with coronary or peripheral artery disease and 591 controls. Acute complications were observed in 33% of women and 16.5% of men. The incidence of complications was the same in both sexes. The most common symptom was dizziness, attributed to the methionine loading. In addition, some subjects also observed drowsiness, nausea, polyuria, and a decrease or increase in blood pressure. Within 30 days after the test, none of the 887 subjects died…
Pharmacodynamics
L-methionine is a major source of sulfur and can prevent hair, skin, and nail diseases; help lower cholesterol levels by increasing the production of lecithin in the liver; reduce liver fat and protect the kidneys; is a natural chelator of heavy metals; regulates ammonia production and produces ammonia-free urine, thereby reducing bladder irritation; affects hair follicles and promotes hair growth. L-Methionine may help combat the toxic effects of hepatotoxic toxins such as acetaminophen. Methionine may have antioxidant activity. It is a sulfur-containing essential amino acid, crucial for many bodily functions. It is a heavy metal chelator. L-Methionine is found in or produced by E. coli (K12 strain, MG1655 strain). Methionine has also been reported in Pinus koraiensis, Cyperus rotundus, and other organisms with relevant data. Methionine is one of the nine essential amino acids for humans (primarily obtained through food) and is essential for growth and tissue repair. As a sulfur-containing amino acid, methionine improves the elasticity and suppleness of skin and hair and strengthens nails. The sulfur provided by methionine participates in various detoxification processes, protects cells from pollutants, slows cellular aging, and is crucial for the absorption and bioavailability of selenium and zinc. Methionine can chelate heavy metals such as lead and mercury, helping them to be excreted from the body. It also has a lipotropic effect, preventing excessive fat accumulation in the liver. (NCI04)
Methionine is a small molecule drug that has completed the most Phase IV clinical trials (covering all indications) and has 12 investigational indications.
Methionine is an essential dietary amino acid, crucial for normal growth and development in humans, other mammals, and birds. Besides serving as a substrate for protein synthesis, it is an intermediate in transmethylation reactions and a major methyl donor in the body, including methyl groups in DNA and RNA intermediates. Methionine is the methyl acceptor for 5-methyltetrahydrofolate-homocysteine methyltransferase (methionine synthase), the only enzyme capable of recycling this form of folate. Methionine is also the methyl acceptor for betaine catabolism. Methionine is also essential for cysteine synthesis. Methionine is considered a metabolic precursor of cysteine. Methionine only transfers sulfur atoms to cysteine; the carbon skeleton of cysteine is provided by serine. The dietary requirements for specific amino acids in disease states are difficult to determine. Protein synthesis requirements in disease states may differ from those in normal states. Requirements in this area can only be assessed when protein synthesis function can be measured and correlated with clinical outcomes. There is currently a consensus on normal requirements for sulfur-containing amino acids (SAAs). The World Health Organization recommends a daily intake of 13 mg/kg for healthy adults. In artificial nutrition regimens, this amount is approximately doubled. Requirements for methionine, cysteine, and taurine may change after illness or trauma. While hypermethioninemia or hyperhomocysteinemia may occur in specific conditions such as congenital enzyme deficiencies, preterm birth, or impaired liver function, supplementation with sulfur-containing amino acids at 2–3 times the minimum recommended daily intake is generally considered safe. The benefits of SAA supplementation have not been established except for certain very specific indications (e.g., acetaminophen poisoning). Methionine is known to exacerbate psychopathological symptoms in patients with schizophrenia, but there is no evidence of a similar effect in healthy subjects. The role of methionine as a precursor to homocysteine is of greatest concern. One study administered a loading dose of methionine (0.1 g/kg) to subjects and used the resulting acute increase in plasma homocysteine as an indicator of susceptibility to cardiovascular disease. Although this method can lead to vascular dysfunction, this dysfunction is acute and unlikely to cause permanent damage. However, accidental ingestion of 10 times the normal dose of methionine resulted in death. Long-term studies in adults have shown that moderate fluctuations in dietary methionine intake do not have adverse consequences, but intake exceeding five times the normal level leads to elevated homocysteine levels. Supplementation with vitamins B6, B12, C, and folic acid can mitigate the effects of methionine on homocysteine and vascular function. Infants consuming 2 to 5 times the normal level of methionine may experience growth retardation and extremely high plasma methionine levels, but no adverse long-term consequences have been observed. Methionine is a sulfur-containing essential L-amino acid that is crucial for many bodily 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.)