Glycidamide is an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

with the formula H₂NC(O)C₂H₃O. It is a colorless, oil. Structurally, it contains adjacent

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it is ...

s and

epoxide In organic chemistry, an epoxide is a cyclic ether () with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for ...

functional group In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the rest ...

s. It is a bioactive, potentially toxic or even carcinogenic metabolite of

acrylonitrile Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid although commercial samples can be yellow due to impurities. It has a pungent odor of garlic or onions. In terms of its molecular ...

and

acrylamide Acrylamide (or acrylic amide) is an organic compound with the chemical formula CH2=CHC(O)NH2. It is a white odorless solid, soluble in water and several organic solvents. From the chemistry perspective, acrylamide is a vinyl-substituted primary ...

. It is a chiral molecule.

Structure and reactivity

Glycidamide is a reactive

metabolite from acrylamide.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. 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. and can react with

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

s. This results in covalent binding of the

electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries ...

. Glycidamide gives a positive response in the

Ames Ames may refer to: Places United States * Ames, Arkansas, a place in Arkansas * Ames, Colorado * Ames, Illinois * Ames, Indiana * Ames, Iowa, the most populous city bearing this name * Ames, Kansas * Ames, Nebraska * Ames, New York * Ames, Ok ...

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

Formation

Early studies showed that glycidamides can be synthesized by the action of

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%� ...

on acrylonitrile derivatives. More relevant to health concerns, glycidamide forms from

. The acrylamide is generated by pyrolysis of proteins rich in

asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...

. Oxidation of acrylamide, catalyzed by the enzyme

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

2E1 (CYP2E1) gives glycidamide.Besaratinia, A., & Pfeifer, G. P. (2004). Genotoxicity of acrylamide and glycidamide. Journal of the National Cancer Institute, 96(13), 1023-1029.

Saturated fatty acids A saturated fat is a type of fat in which the fatty acid chains have all single bonds. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone and fatty acids that each contain a long linear or branched ch ...

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.

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). Glycidamide also reacts with haemoglobine (Hb) to form a

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

adduct An adduct (from the Latin ''adductus'', "drawn toward" alternatively, a contraction of "addition product") is a product of a direct addition of two or more distinct molecules, resulting in a single reaction product containing all atoms of all co ...

, S-(20hydroxy-2carboxyethyl)cysteine.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. With this reaction, N-terminal valine adducts are also formed.

Mechanism of action

According to a major review, acrylamide "is extensively metabolized, mostly by conjugation with

glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pero ...

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."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. Glycidamide inhibits the sodium/potassium ATPase protein present in the plasma membrane of nerve cells. Intracellular sodium increases and intracellular potassium decreases due to this inhibition. This causes

depolarization In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is esse ...

of the nerve membrane. The depolarization triggers a reverse sodium/calcium exchange, which will cause calcium-mediated axon degeneration.

Metabolism

The liver is a very active organ in the

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

xenobiotic A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual. Natural compo ...

s. Substances in the liver modify the compounds to make them more soluble in water, in order to excrete them through

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...

and

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excretion, excreted from the body through the urethra. Cel ...

. In the case of acrylamide, this metabolic strategy result in a greater

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...

of the compound. 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

transferase A transferase is any one of a class of enzymes that catalyse the transfer of specific functional groups (e.g. a methyl or glycosyl group) from one molecule (called the donor) to another (called the acceptor). They are involved in hundreds of di ...

s, 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. Glycidamide can also be

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

to glyceramide both spontaneously or enzymatically by microsomal epoxide hydrolase. This too can be excreted through urine.

Animal studies

Mice and rats show mutations and DNA adducts consistent with those arising from glycidamide. Another study found tumors in the mice bodies after treatment with glycidamideVon 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. A study by

National Toxicology Program The National Toxicology Program (NTP) is an inter-agency program run by the United States Department of Health and Human Services to coordinate, evaluate, and report on toxicology within public agencies. The National Toxicology Program is headqua ...

(2014)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 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

carcinoma Carcinoma is a malignancy that develops from epithelial cells. Specifically, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that arises from cells originating in the endodermal, mesodermal ...

fibroadenoma Fibroadenomas are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules (milk producing glands) and ducts (tubes that carry the milk to the nipple). These are surrounded by glandular, ...

s and malignant mesotheliomas.

References

{{Medicine Carboxamides Epoxides