Glycidamide

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless, oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide.[2][3] It is a chiral molecule.

Glycidamide
Names
Preferred IUPAC name
Oxiranecarboxamide
Other names
Glycidic acid amide
Oxirane-2-carboxamide
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.024.694
PubChem CID
UNII
InChI
  • InChI=1S/C3H5NO2/c4-3(5)2-1-6-2/h2H,1H2,(H2,4,5)
SMILES
  • C1C(O1)C(=O)N
Properties
Chemical formula
 C3H5NO2
Molar mass 87.078 g·mol−1
Density 1.404 g/cm3[1]
Melting point 32–34 °C (90–93 °F; 305–307 K)
Pharmacology
Pharmacokinetics:
5 hours
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Structure and reactivity

Glycidamide is a reactive epoxide metabolite from acrylamide.[4] [5] and can react with nucleophiles. This results in covalent binding of the electrophile.[6]

Glycidamide gives a positive response in the Ames/Salmonella mutagenicity assay, which indicates that it can cause mutations in the DNA.[4] However, " Epidemiologic studies of workers for possible health effects from exposures to acrylamide have not shown a consistent increase in cancer risk."[7]

Formation

Early studies showed that glycidamides can be synthesized by the action of hydrogen peroxide on acrylonitrile derivatives.[8]

More relevant to health concerns, glycidamide forms from acrylamide. The acrylamide is generated by pyrolysis of proteins rich in asparagine. Oxidation of acrylamide, catalyzed by the enzyme cytochrome P450 2E1 (CYP2E1) gives glycidamide.[9]Saturated fatty acids protect the acrylamide from forming glycidamide. When during food processing, oil is used that contains unsaturated fatty acids, the amount of glycidamide formed is much higher.[10]

Pathology

Reactions

Glycidamide reacts with DNA to form adducts. It is more reactive toward DNA than acrylamide. Several glycidamide-DNA adducts have been characterized. The main DNA adducts are N7-(2-carbamoyl-2-hydroxyethyl)-guanine (or N7-GA-Gua) and N3-(2-carbamoyl-2-hydroxyethyl)adenine (or N3-GA-Ade).[7] Glycidamide also reacts with haemoglobine (Hb) to form a cysteine adduct, S-(20hydroxy-2carboxyethyl)cysteine.[6] With this reaction, N-terminal valine adducts are also formed.[11]

Mechanism of action

According to a major review, acrylamide "is extensively metabolized, mostly by conjugation with glutathione but also by epoxidation to glycidamide (GA). Formation of GA is considered to represent the route underlying the genotoxicity and carcinogenicity of acrylamide. The reaction of glycidamide and glutathione represents a detoxification pathway."[12][5][13]

Glycidamide inhibits the sodium/potassium ATPase protein present in the plasma membrane of nerve cells.[14] Intracellular sodium increases and intracellular potassium decreases due to this inhibition. This causes depolarization of the nerve membrane. The depolarization triggers a reverse sodium/calcium exchange, which will cause calcium-mediated axon degeneration.[15]

Metabolism

The liver is a very active organ in the metabolism of xenobiotics. Substances in the liver modify the compounds to make them more soluble in water, in order to excrete them through bile and urine. In the case of acrylamide, this metabolic strategy result in a greater toxicity of the compound.[16] Whether this is the case for glycidamide remains unclear.

Glycidamide can be detoxified through diverse pathways such as the formation of glycidamide-glutathione conjugates. Both an enzymatic pathway via glutathione-S-transferase and a non-enzymatic pathway exist. These glycidamide-glutathione conjugates are further metabolized to mercapturic acids by various peptidases and transferases, such as gamma-glutamyl-transpeptidase, dipeptidase, and N-acetyltransferase. The mercapturic acids that can be formed are N-acetyl-S-(2-carbamoylethyl)-cysteine (AAMA), N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-cysteine (GAMA2), and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-cysteine (GAMA3) (Huang et al., 2011). These mercapturic acids are excreted through urine.[13]

Glycidamide can also be hydrolyzed to glyceramide both spontaneously or enzymatically by microsomal epoxide hydrolase.[13] This too can be excreted through urine.[6]

Animal studies

Mice and rats show mutations and DNA adducts consistent with those arising from glycidamide.[9][17][18] Another study found tumors in the mice bodies after treatment with glycidamide[19] A study by National Toxicology Program (2014)[20] provided evidence of carcinogenic activity of glycidamide in several species of rats and mice. For two years, rats and mice were exposed to varying doses of glycidamide in drinking water. In the rats and mice were several carcinogenic effects found, such as carcinomas, fibroadenomas and malignant mesotheliomas.

References
  1. Hemgesberg, Melanie N.; Bonck, Thorsten; Merz, Karl-Heinz; Sun, Yu; Schrenk, Dieter (2016). "Crystal Structure of Glycidamide: The Mutagenic and Genotoxic Metabolite of Acrylamide". Acta Crystallographica Section E. 72 (8): 1179–1182. doi:10.1107/S2056989016010859. PMC 4971867. PMID 27536408.
  2. Friedman, Mendel (2003). "Chemistry, Biochemistry, and Safety of Acrylamide. A Review". Journal of Agricultural and Food Chemistry. 51 (16): 4504–4526. doi:10.1021/jf030204+. PMID 14705871.
  3. Mendel Friedman, Don Mottram, ed. (2005). Chemistry and Safety of Acrylamide in Food. ISBN 978-1-4419-3672-1.
  4. Bergmark, E., Calleman, C. J., & Costa, L. G. (1991). Formation of hemoglobin adducts of acrylamide and its epoxide metabolite glycidamide in the rat. Toxicology and Applied Pharmacology, 111(2), 352-363.
  5. Beland, F. A., Olson, G. R., Mendoza, M. C., Marques, M. M., & Doerge, D. R. (2015). Carcinogenicity of glycidamide in B6C3F 1 mice and F344/N rats from a two-year drinking water exposure. Food and Chemical Toxicology, 86, 104-115.
  6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. "Acrylamide" in IARC Monographs on the evaluation of carcinogen risk to humans, International Agency for Research on Cancer, Lyon, France, 1994, 60:389–433.
  7. Klaunig, James E. (2008). "Acrylamide Carcinogenicity". Journal of Agricultural and Food Chemistry. 56 (15): 5984–5988. doi:10.1021/jf8004492. PMID 18624430.
  8. Murray, J. V.; Cloke, J. B. (1934). "The Formation of Glycidamides by the Action of Hydrogen Peroxide on α, β-Ethylenic Nitriles". Journal of the American Chemical Society. 56 (12): 2749-2751. doi:10.1021/ja01327a070.
  9. Besaratinia, A., & Pfeifer, G. P. (2004). Genotoxicity of acrylamide and glycidamide. Journal of the National Cancer Institute, 96(13), 1023-1029.
  10. Granvogl, M., Koehler, P., Latzer, L., & Schieberle, P. (2008). Development of a stable isotope dilution assay for the quantitation of glycidamide and its application to foods and model systems. Journal of agricultural and food chemistry, 56(15), 6087-6092.
  11. Schettgen, T., Müller, J., Fromme, H., & Angerer, J. (2010). Simultaneous quantification of haemoglobin adducts of ethylene oxide, propylene oxide, acrylonitrile, acrylamide and glycidamide in human blood by isotope-dilution GC/NCI-MS/MS. Journal of Chromatography B 878(27), 2467-2473.
  12. "Scientific Opinion on Acrylamide in Food". EFSA Journal. 13 (6). 2015. doi:10.2903/j.efsa.2015.4104.
  13. Luo, Y. S., Long, T. Y., Shen, L. C., Huang, S. L., Chiang, S. Y., & Wu, K. Y. (2015). Synthesis, characterization and analysis of the acrylamide-and glycidamide-glutathione conjugates. Chemico-Biological Interactions, 237, 38-46.
  14. Lehning, E. J., Persaud, A., Dyer, K. R., Jortner, B. S., & LoPachin, R. M. (1998). Biochemical and morphologic characterization of acrylamide peripheral neuropathy. Toxicology and Applied Pharmacology, 151(2), 211-221.
  15. LoPachin, R. M., & Lehning, E. J. (1997). Mechanism of calcium entry during axon injury and degeneration. Toxicology and Applied Pharmacology, 143(2), 233-244.
  16. Kurebayashi, H., & Ohno, Y. (2006). Metabolism of acrylamide to glycidamide and their cytotoxicity in isolated rat hepatocytes: protective effects of GSH precursors. Archives of Toxicology, 80(12), 820-828.
  17. Manjanatha, M.G., Aidoo, A., Shelton, S.D., Bishop, M.E., McDaniel, L.P., Lyn-Cook, L.E. & Doerge D.R. (2006). Genotoxicity of acrylamide and its metabolite glycidamide administered in drinking water to male and female Big Blue mice. Environ Mol Mutagen;47:6–17
  18. Mei, N., McDaniel, L.P., Dobrovolsky, V.N., Guo, X., Shaddock, J.G., Mittelstaedt, R.A., Azuma, M., Shelton, S.D., McGarrity, L.J., Doerge, D.R. & Heflich, R.H. (2010). The genotoxicity of acrylamide and glycidamide in Big Blue rats. Toxicol Sci; 115:412–21
  19. Von Tungeln, L. S., Doerge, D. R., Gamboa da Costa, G., Matilde Marques, M., Witt, W. M., Koturbash, I., Pogribny, I.P. & Beland, F. A. (2012). Tumorigenicity of acrylamide and its metabolite glycidamide in the neonatal mouse bioassay.International Journal of Cancer, 131(9), 2008-2015.
  20. National Toxicology Program. (2014). NTP Technical Report on the Toxicology and Carcinogenesis: Studies of Glycidamide. Retrieved on March 11, 2016, from http://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr588_508.pdf
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