Trimethylamine oxide

Relevant Data

Food Additives Approved in the United States:

Food Additives Approved by WHO:

General Information

Chemical nameTrimethylamine oxide
CAS number1184-78-7
COE number10494
JECFA number1614
Flavouring typesubstances
FL No.11.025
MixtureNo
Purity of the named substance at least 95% unless otherwise specified
Reference bodyEFSA

From webgate.ec.europa.eu

Computed Descriptors

Download SDF
2D Structure
CID1145
IUPAC NameN,N-dimethylmethanamine oxide
InChIInChI=1S/C3H9NO/c1-4(2,3)5/h1-3H3
InChI KeyUYPYRKYUKCHHIB-UHFFFAOYSA-N
Canonical SMILESC[N+](C)(C)[O-]
Molecular FormulaC3H9NO
Wikipediatrimethylamine oxide

From Pubchem

Computed Properties

Property Name Property Value
Molecular Weight75.111
Hydrogen Bond Donor Count0
Hydrogen Bond Acceptor Count1
Rotatable Bond Count0
Complexity28.4
CACTVS Substructure Key Fingerprint A A A D c c B C I A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A F A A E A A A A A A A A A A Q C A A M Q A A A A A A A A A A A A A A A A A A A A A A A I A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A = =
Topological Polar Surface Area18.1
Monoisotopic Mass75.068
Exact Mass75.068
XLogP3None
XLogP3-AA-0.3
Compound Is CanonicalizedTrue
Formal Charge0
Heavy Atom Count5
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Isotope Atom Count0
Covalently-Bonded Unit Count1

From Pubchem

Food Additives Biosynthesis/Degradation

Toxicity Profile

Route of ExposureEndogenous, Ingestion
Mechanism of ToxicityUremic toxins such as TMAO are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (5). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (6). TMAO appears to contribute to the development of atherosclerosis in part by promoting cholesterol accumulation within macrophages, perhaps by inducing scavenger receptors such as CD36 and SRA1, both of which are involved in the uptake of modified lipoproteins .
MetabolismTrimethylamine-N-oxide is biosynthesized in the liver from trimethylamine (TMA), which is derived from choline. Flavin monooxygenase 3 (FMO3) has been implicated in the oxidation of TMA since individuals with mutations in FMO3 present with accumulation of TMA levels, causing fish malodor syndrome. TMAO is secreted in the urine and is not metabolized any further.
Toxicity Values>100 uM in blood is usually indicative of uremia
Lethal Dose
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Minimum Risk Level>75 uM in blood
Health EffectsHigh endogenous levels of TMAO in the blood (>100 uM) can lead to uremia which can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease. Chronically high levels of TMAO in the blood can also lead to the development of atherosclerosis and atherosclerotic plaques.
TreatmentKidney dialysis is usually needed to relieve the symptoms of uremic syndrome until normal kidney function can be restored. Treatments for atherosclerosis may include lifestyle changes (exercise, eating fruits and vegetables), medicines (statins), and medical procedures or surgery (angioplasty).
Reference
  1. Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A: Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012 Jul;23(7):1258-70. doi: 10.1681/ASN.2011121175. Epub 2012 May 24.[22626821 ]
  2. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL: Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.1056/NEJMoa1109400.[23614584 ]
  3. Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL: Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922.[21475195 ]
  4. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, Britt EB, Fu X, Wu Y, Li L, Smith JD, DiDonato JA, Chen J, Li H, Wu GD, Lewis JD, Warrier M, Brown JM, Krauss RM, Tang WH, Bushman FD, Lusis AJ, Hazen SL: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013 May;19(5):576-85. doi: 10.1038/nm.3145. Epub 2013 Apr 7.[23563705 ]
  5. Silwood CJ, Lynch E, Claxson AW, Grootveld MC: 1H and (13)C NMR spectroscopic analysis of human saliva. J Dent Res. 2002 Jun;81(6):422-7.[12097436 ]
  6. Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297.[25041433 ]
  7. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461.[22419041 ]
  8. Nicholson JK, Foxall PJ, Spraul M, Farrant RD, Lindon JC: 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem. 1995 Mar 1;67(5):793-811.[7762816 ]
  9. Sweatman BC, Farrant RD, Holmes E, Ghauri FY, Nicholson JK, Lindon JC: 600 MHz 1H-NMR spectroscopy of human cerebrospinal fluid: effects of sample manipulation and assignment of resonances. J Pharm Biomed Anal. 1993 Aug;11(8):651-64.[8257730 ]
  10. Messana I, Forni F, Ferrari F, Rossi C, Giardina B, Zuppi C: Proton nuclear magnetic resonance spectral profiles of urine in type II diabetic patients. Clin Chem. 1998 Jul;44(7):1529-34.[9665433 ]
  11. Maschke S, Wahl A, Azaroual N, Boulet O, Crunelle V, Imbenotte M, Foulard M, Vermeersch G, Lhermitte M: 1H-NMR analysis of trimethylamine in urine for the diagnosis of fish-odour syndrome. Clin Chim Acta. 1997 Jul 25;263(2):139-46.[9246418 ]
  12. Kenyon S, Carmichael PL, Khalaque S, Panchal S, Waring R, Harris R, Smith RL, Mitchell SC: The passage of trimethylamine across rat and human skin. Food Chem Toxicol. 2004 Oct;42(10):1619-28.[15304308 ]
  13. Thithapandha A: A pharmacogenetic study of trimethylaminuria in Orientals. Pharmacogenetics. 1997 Dec;7(6):497-501.[9429235 ]
  14. On SL, Holmes B: Effect of inoculum size on the phenotypic characterization of Campylobacter species. J Clin Microbiol. 1991 May;29(5):923-6.[2056060 ]
  15. Shepshelovich J, Goldstein-Magal L, Globerson A, Yen PM, Rotman-Pikielny P, Hirschberg K: Protein synthesis inhibitors and the chemical chaperone TMAO reverse endoplasmic reticulum perturbation induced by overexpression of the iodide transporter pendrin. J Cell Sci. 2005 Apr 15;118(Pt 8):1577-86. Epub 2005 Mar 22.[15784681 ]
  16. Podadera P, Sipahi AM, Areas JA, Lanfer-Marquez UM: Diagnosis of suspected trimethylaminuria by NMR spectroscopy. Clin Chim Acta. 2005 Jan;351(1-2):149-54.[15563884 ]
  17. Wolrath H, Stahlbom B, Hallen A, Forsum U: Trimethylamine and trimethylamine oxide levels in normal women and women with bacterial vaginosis reflect a local metabolism in vaginal secretion as compared to urine. APMIS. 2005 Jul-Aug;113(7-8):513-6.[16086821 ]
  18. Watt K, Jess TJ, Kelly SM, Price NC, McEwan IJ: Induced alpha-helix structure in the aryl hydrocarbon receptor transactivation domain modulates protein-protein interactions. Biochemistry. 2005 Jan 18;44(2):734-43.[15641800 ]
  19. Chung YL, Rider LG, Bell JD, Summers RM, Zemel LS, Rennebohm RM, Passo MH, Hicks J, Miller FW, Scott DL: Muscle metabolites, detected in urine by proton spectroscopy, correlate with disease damage in juvenile idiopathic inflammatory myopathies. Arthritis Rheum. 2005 Aug 15;53(4):565-70.[16082628 ]
  20. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ: Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013 Jan 8;17(1):49-60. doi: 10.1016/j.cmet.2012.12.011.[23312283 ]

From T3DB

Taxonomic Classification

KingdomOrganic compounds
SuperclassOrganic nitrogen compounds
ClassOrganonitrogen compounds
SubclassAminoxides
Intermediate Tree NodesNot available
Direct ParentTrialkyl amine oxides
Alternative Parents
Molecular FrameworkAliphatic acyclic compounds
SubstituentsTrialkyl amine oxide - Trisubstituted n-oxide - N-oxide - Organic oxygen compound - Organopnictogen compound - Organic oxide - Hydrocarbon derivative - Aliphatic acyclic compound
DescriptionThis compound belongs to the class of organic compounds known as trialkyl amine oxides. These are hydrocarbyl derivatives of the aminoxide anion, with the general formula R3N+[O-] or R3N=O, where R is an alkyl group.

From ClassyFire

Targets

Target Details

Klotho

General Function:
Vitamin d binding
Specific Function:
May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity).The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
Gene Name:
KL
Uniprot ID:
Q9UEF7
Molecular Weight:
116179.815 Da
References
  1. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
Target Details

NADPH oxidase 4

General Function:
Superoxide-generating nadph oxidase activity
Specific Function:
Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Gene Name:
NOX4
Uniprot ID:
Q9NPH5
Molecular Weight:
66930.995 Da
References
  1. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
Target Details

Solute carrier family 22 member 8

General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:
SLC22A8
Uniprot ID:
Q8TCC7
Molecular Weight:
59855.585 Da
References
  1. Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]

From T3DB