S-adenosyl-L-methionine (SAMe) acts through multiple molecular targets, including: - DNA methyltransferases (DNMTs) (e.g., DNMT1, DNMT3A) in cancer cells, where it modulates DNA methylation and enhances 5-fluorouracil (5-FU) efficacy . - Histone deacetylases (HDACs) and methyltransferases in epigenetic regulation of gene expression, particularly in liver disease and cancer .

In Cal-33 and JHU-SCC-011 cells, S-adenosyl-L-methionine (300 µM, 24 or 48 hours) activates cells and encourages cell cycle marketing [4]. S-adenosyl-L-methionine (300 S-adenosyl-L-methionine (5–40 μg/mL, 48 h) inhibits Cal–33 and JHU-SCC-011 cell migration while protecting 5‑FU migration by controlling DNMT expression (μM, 24 h) [4]. Analysis of apoptosis [4]

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1. Antiproliferative Activity: - In human A549 lung cancer cells, SAMe (1–10 mM) combined with 5-FU (10 μM) significantly reduced cell viability compared to 5-FU alone, as measured by MTT assay. This effect was associated with upregulation of DNMTs expression, enhancing DNA methylation and apoptosis . - In head and neck squamous cancer cells (CAL-33 and JHU-SCC-011), SAMe (0.5–2 mM) dose-dependently inhibited cell migration and invasion, as assessed by Transwell and Matrigel assays. Western blot analysis revealed downregulation of AKT and β-catenin signaling pathways . 2. Enzyme Modulation: - SAMe (1–10 μM) increased DNMTs activity in A549 cells, protecting the anticancer effect of 5-FU by stabilizing DNA methylation patterns . - In synovial cells, SAMe (10–100 μM) restored TNF-α-induced reduction in proteoglycan synthesis, suggesting chondroprotective effects in osteoarthritis .

S-adenosyl-L-methionine (30 mg/kg, facial, for 3 days) prevents ASD-like behaviors caused by valproic acid exposure in early postnatal rats [6]. S-adenosyl-L-methionine (50 and 100)

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1. Tumor Growth Inhibition: - In athymic nude mice bearing A549 lung tumors, SAMe (100 mg/kg/day, oral) combined with 5-FU (20 mg/kg, intraperitoneal) significantly reduced tumor volume compared to 5-FU alone. Histological analysis showed increased necrosis and reduced Ki-67 staining . 2. Neuroprotective Effects: - In a valproic acid (VPA)-induced autism-like mouse model, SAMe (30 mg/kg/day, oral) prevented social deficits and repetitive behaviors, with normalization of oxidative stress markers (e.g., SOD, catalase) in the prefrontal cortex . 3. Antiepileptic Effects: - In pentylenetetrazole (PTZ)-kindled rats, SAMe (100 mg/kg, intraperitoneal) prolonged seizure latency and reduced seizure severity. Memory impairment was reversed, as demonstrated by improved performance in the elevated plus maze test .

1. DNMTs Activity Assay: - A549 cell lysates were incubated with SAMe (1–10 μM) and [³H]-methyl-SAMe. DNA methylation was quantified by liquid scintillation counting. SAMe increased DNMTs activity in a dose-dependent manner, with maximal effect at 5 μM . 2. Antioxidant Enzyme Assay: - Brain homogenates from VPA-exposed mice treated with SAMe were analyzed for SOD and catalase activity. SAMe restored enzyme activity to control levels, indicating antioxidant effects .

Apoptosis analysis [4]
Cell Types: Cal-33 and JHU-SCC-011 cells
Tested Concentrations: 300 μM
Incubation Duration: 24 hrs (hours) (Cal-33) or 48 hrs (hours) ( HU-SCC-011) results. Anti-cancer effect [5].
Experimental Results: demonstrated approximately 10% and 3% of apoptotic cells respectively.

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Cell cycle analysis [4]
Cell Types: Cal-33 and JHU-SCC-011 Cell
Tested Concentrations: 300 µM
Incubation Duration: 24 hrs (hours) (Cal-33) or 48 hrs (hours) (HU-SCC-011)
Experimental Results: Cyclin expression diminished B1, E1, and D1 in Cal-33 and JHU-SCC-011 cells.

Animal/Disease Models: Valproic acid-treated young rats [6]
Doses: 30 mg/kg
Route of Administration: Oral for 3 days
Experimental Results: Remission of most autism spectrum disorders (ASD)-like neurobehavioral symptoms. Normalizes redox potential in the prefrontal cortex.

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1. Tumor Xenograft Model: - A549 cells (5 × 10⁶) were implanted subcutaneously in nude mice. SAMe (100 mg/kg) was administered orally daily, and 5-FU (20 mg/kg) intraperitoneally twice weekly. Tumor volume was measured twice weekly using calipers . 2. Autism-like Mouse Model: - Neonatal ICR mice received VPA (300 mg/kg, intraperitoneal) on postnatal day 4. SAMe (30 mg/kg) was administered orally from day 5 to 7. Behavioral tests (e.g., social interaction, marble burying) were conducted at day 50 . 3. PTZ-Kindling Model: - Male Wistar rats received PTZ (35 mg/kg, intraperitoneal) every other day for 14 days to induce kindling. SAMe (100 mg/kg) was administered intraperitoneally 30 minutes before PTZ. Seizure severity was scored using Racine’s scale, and memory was assessed via elevated plus maze .

Absorption, Distribution and Excretion
Following oral administration, S-adenosylmethionine is absorbed via the small intestine. Since food affects absorption, it is best taken on an empty stomach. Oral bioavailability is low. Metabolism/Metabolites Significant first-pass metabolism occurs in the liver. Approximately 50% of S-adenosylmethionine (SAMe) is metabolized in the liver. SAMe is metabolized to S-adenosylhomocysteine, which is further metabolized to homocysteine. Homocysteine can be metabolized to cystathionine, then to cysteine, or to methionine. The cofactor for homocysteine to cysteine is vitamin B6. The cofactors for homocysteine to methionine are folic acid, vitamin B12, and betaine. 1. Absorption: - Due to extensive first-pass metabolism in the liver, the oral bioavailability of SAMe is low (approximately 5-10%). 1. Peak Plasma Concentration (Cmax): 2.1 ± 0.3 μM one hour after oral administration of SAMe (100 mg/kg). 2. Distribution: SAMe readily crosses the blood-brain barrier; the brain/plasma concentration ratio in mice is 0.8–1.2. 3. Metabolism: SAMe is metabolized by methyltransferases to S-adenosylhomocysteine (SAH), which is further metabolized to homocysteine. 4. Excretion: Approximately 70–80% of the dose is excreted in the urine as metabolites within 24 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
SAM-e (S-adenosylmethionine) is a naturally occurring methyl radical donor involved in enzymatic transmethylation reactions in humans and animals. SAM-e has no specific lactation-related use, but it has been used to treat postpartum depression, cholestatic jaundice, osteoarthritis, and many other conditions. SAM-e has low oral bioavailability. SAM-e is generally well tolerated in adults. The most common adverse reactions are gastrointestinal reactions, such as nausea. Skin rashes have also been reported. There is currently no clinical information regarding the use of SAM-e during lactation. However, it is not expected that SAM-e taken by breastfeeding mothers will have any adverse effects on breastfed infants, especially if the infant is older than 2 months. Dietary supplements do not require extensive premarket approval from the U.S. Food and Drug Administration (FDA). Manufacturers are responsible for ensuring the safety of their products but are not required to demonstrate the safety and efficacy of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and there is often a difference between the ingredients listed on the label and the actual ingredients or amounts. Manufacturers may commission independent agencies to verify the quality of their products or their ingredients, but this does not necessarily mean that the product has been certified safe or effective. Given the above issues, clinical trial results for one product may not apply to other products. For more detailed information on dietary supplements, please visit other pages on the LactMed website.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Toxicity Overview
S-adenosylmethionine (SAMe) is a naturally occurring substance found in human cells. It is a direct metabolite of the essential amino acid L-methionine. SAMe plays an important biochemical role in the body, providing a single-carbon methyl group through a process called transmethylation. SAMe is produced by the reaction of L-methionine and Adenanthin triphosphate (ATP) catalyzed by S-adenosylmethionine synthase. It is a methyl donor in the biosynthesis of DNA and RNA nucleic acids, phospholipids, proteins, adrenaline, melatonin, creatine, and other molecules. 1. Acute Toxicity: - The oral LD₅₀ of SAMe in mice is > 5 g/kg, and no significant adverse reactions were observed at doses up to 1000 mg/kg. - A single oral dose of SAMe (1000 mg/kg) in rats caused transient gastrointestinal discomfort, but no organ damage was observed. 2. Chronic Toxicity: - Long-term (6 months) oral administration of SAMe (200 mg/kg/day) in dogs did not show any abnormalities in hematological or biochemical indicators. 3. Drug Interactions: - SAMe may enhance the hepatotoxicity of methotrexate in rats by competing with hepatic transport proteins.

[1]. G M Bressa. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.

[2]. S-adenosyl methionine (SAMe) versus celecoxib for the treatment of osteoarthritis symptoms: a double-blind cross-over trial. [ISRCTN36233495]. BMC Musculoskelet Disord. 2004 Feb 26;5:6.

[3]. S-adenosylmethionine in liver health, injury, and cancer. Physiol Rev. 2012 Oct;92(4):1515-42.

[4]. Effects of S‑adenosyl‑L‑methionine on the invasion and migration of head and neck squamous cancer cells and analysis of the underlying mechanisms. Int J Oncol. 2020 May;56(5):1212-1224.

[5]. S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells. Mol Clin Oncol. 2013 Mar;1(2):373-378.

[6]. S-adenosyl methionine prevents ASD like behaviors triggered by early postnatal valproic acid exposure in very young mice. Neurotoxicol Teratol. 2019 Jan-Feb;71:64-74.

[7]. Evaluation of antiepileptic effect of S-adenosyl methionine and its role in memory impairment in pentylenetetrazole-induced kindling model in rats. Epilepsy Behav. 2016 Aug;61:153-157.

S-Adenosyl-L-methionine is a sulfobetaine, the conjugate base of S-Adenosyl-L-methionine, obtained by deprotonation of the carboxyl group. It is a human metabolite functionally related to L-methionine. It is a physiological methyl radical donor, participating in enzymatic transmethylation reactions, and is present in all organisms. It has anti-inflammatory activity and has been used to treat chronic liver disease. (Excerpt from Merck, 11th edition) S-Adenosylmethionine is a metabolite present in or produced by Escherichia coli (K12 strain, MG1655 strain). It has been reported that S-Adenosylmethionine exists in humans and peas, and relevant data are available. S-Adenosylmethionine is a nutritional supplement synthesized from Adenanthin triphosphate (ATP) and the amino acid methionine by the endogenous essential enzyme methionine adenosyltransferase (MAT), and has potential antitumor activity. S-Adenosylmethionine (SAMe) can act as a methyl donor in various transmethylation reactions after administration. In cancer cells, this substance can induce methylation of pro-tumorigenic genes, reverse DNA hypomethylation, and inhibit oncogene transcription. This can induce apoptosis in susceptible tumor cells and inhibit their proliferation. A physiological methyl radical donor, participating in enzymatic transmethylation reactions, it is present in all organisms. It has anti-inflammatory activity and has been used to treat chronic liver disease. (Excerpt from Merck, 11th edition) See also: S-Adenosyl-L-methionine disulfide toluenesulfonate (active moiety); S-Adenosylmethionine chloride (active moiety). Drug Indications S-Adenosylmethionine (SAMe) is used in Europe as a treatment for depression, liver disease, fibromyalgia, and osteoarthritis. It has also been introduced to the US market as a dietary supplement to support bone and joint health, as well as mood and emotional well-being. Mechanism of Action S-Adenosylmethionine (SAMe) is a naturally occurring substance found in human cells. It is a direct metabolite of the essential amino acid L-methionine. SAMe plays a crucial biochemical role in the body, providing a single-carbon methyl group through a process called transmethylation. SAMe is produced by the reaction of L-methionine and Adenanthin triphosphate (ATP) catalyzed by S-adenosylmethionine synthase, and is a methyl donor in the biosynthesis of DNA and RNA nucleic acids, phospholipids, proteins, adrenaline, melatonin, creatine, and other molecules.

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Pharmacodynamics
S-adenosylmethionine is an intermediate metabolite of methionine. It participates in methylation processes, contributing to cell growth and repair, and maintaining the phospholipid bilayer in cell membranes. It also helps maintain the activity of various hormones and neurotransmitters that affect mood. It is found in the highest concentrations in the brain and liver.

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- Mechanism of Action: SAMe acts as a methyl donor for DNA, histones, and neurotransmitters, regulating epigenetic processes and redox balance. In cancer, it enhances cellular sensitivity to chemotherapy by regulating DNMTs. - Clinical Applications: Approved in Europe for the treatment of depression, osteoarthritis, and liver disease; marketed in the United States as a dietary supplement. - FDA Status: Not approved as a drug in the United States, but regulated as a dietary supplement. The FDA has no specific warnings regarding the use of SAMe alone, but interactions with antidepressants (such as SSRIs) may increase serotonin levels. - Preclinical Efficacy: SAMe showed a synergistic effect with 5-FU in a lung cancer model and prevented autistic-like behaviors in mice.

C15H22N6O5S

398.438

398.137

C, 45.22; H, 5.57; N, 21.09; O, 20.08; S, 8.05

29908-03-0

S-Adenosyl-L-methionine tosylate;52248-03-0;S-Adenosyl-L-methionine-d3;68684-40-2;S-Adenosyl-L-methionine disulfate tosylate;97540-22-2;S-Adenosyl-L-methionine iodide;3493-13-8;S-Adenosyl-L-methionine (1,4-butanedisulfonate);200393-05-1;S-Adenosyl-L-methionine-13C;74084-24-5

34755

Off-white to light yellow solid powder

247-249ºC

-2.8

4

10

6

27

527

5

C[S+](CC[C@@H](C(=O)[O-])N)C[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=NC3=C(N=CN=C32)N)O)O

MEFKEPWMEQBLKI-AIRLBKTGSA-N

InChI=1S/C15H22N6O5S/c1-27(3-2-7(16)15(24)25)4-8-10(22)11(23)14(26-8)21-6-20-9-12(17)18-5-19-13(9)21/h5-8,10-11,14,22-23H,2-4,16H2,1H3,(H2-,17,18,19,24,25)/t7-,8+,10+,11+,14+,27?/m0/s1

(2S)-2-amino-4-((((2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(methyl)sulfonio)butanoate

S-adenosylmethionine; MSI195; AdoMet; S-adenosylmethionine; Active methionine; S-adenosyl methionine; Adenosine, 5'-((3-amino-3-carboxypropyl)methylsulfonio)-5'-deoxy-, inner salt, (3S)-; DTXSID6032019; S-adenosyl-methionine; S Adenosylmethionine; ...; 29908-03-0; MSI-195; SAMeMSI 195; Ademetionine; Heptral Gumbaral.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

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

DMSO : ~100 mg/mL (~250.98 mM)
H2O : ≥ 43 mg/mL (~107.92 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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