Ethionine: Difference between revisions
Content deleted Content added
remove bunch of unencyclopedic content that is WP:OR, assembled from primary sources |
|||
| Line 39: | Line 39: | ||
}} |
}} |
||
}} |
}} |
||
'''Ethionine''' is an analogue of the essential amino acid [[methionine]]. It has an [[Ethyl group|ethyl]] group where methionine has a methyl group. Unlike methionine, ethionine is known to be a hepatotoxin. The molecule also induces several other pathologies. Ethionine is an [[antimetabolite]] and methionine [[Receptor antagonist|antagonist]]. It prevents amino acid incorporation into proteins and interferes with cellular use of [[adenosine triphosphate]] (ATP). Because of these pharmacological effects, ethionine is highly toxic and is a potent [[carcinogen]]. Some of these toxic effects may be reversed by the administration of methionine.<ref name=":0">Timbrell JA. 2008. Biochemical mechanisms of toxicity. Principles of biochemical toxicology, fourth edition. CRC Press. p. 293-407.</ref> However, when continuously administered, ethionine is lethal. |
|||
'''Ethionine''' is a [[Proteinogenic amino acid|non-proteinogenic]] [[amino acid]] structurally related to [[methionine]], with an [[ethyl group]] in place of the [[methyl group]]. |
|||
== History == |
|||
Ethionine was first synthesized by Dyer in 1938. She tested rats on a diet with and without ethionine. She stated that the rats with the ethionine/[[casein]] diet lost weight rapidly. She also discovered that this effect could be reversed when methionine was added as well. Several years later, du Vigneaud discovered that ethionine was just as toxic when given in a diet with amino acids and choline.<ref>Du Vigneaud V. 1941. Interrelationships between choline and other methylated compounds. Biol Symposia.</ref> Harris and Kohn (1941) observed growth inhibition by ethionine within [[Escherichia coli|E. Coli]], this could also be counteracted with methionine.<ref>HARRIS JS, KOHN HI. 1941. On the mode of action of the sulfonamides ii. The specific antagonism between methionine and the sulfonamides in escherichia coli. Journal of Pharmacology and Experimental Therapeutics. 73(4):383-400.</ref> Throughout the following years more and more research was done to prove the toxicity, carcinogenicity and pathology of ethionine.<ref name=":1">Farber E. 1963. Ethionine carcinogenesis*†. In: Alexander H, Sidney W, editors. Advances in cancer research. Academic Press. p. 383-474.</ref> |
|||
[[File:Ethionine.png|left|thumb|242x242px|Chemical structure of ethionine]] |
|||
Ethionine is an [[antimetabolite]] and methionine [[Receptor antagonist|antagonist]]. It prevents amino acid incorporation into proteins and interferes with cellular use of [[adenosine triphosphate]] (ATP). Because of these pharmacological effects, ethionine is highly toxic and is a potent carcinogen.<ref>{{cite journal|title=Hypomethylation of DNA in ethionine-fed rats|author=Narayan Shivapurkar, Mary J. Wilson and Lionel A. Poirier |journal=Carcinogenesis|volume =5|issue=8|pages=989–992|year=1984|doi=10.1093/carcin/5.8.989|pmid=6744518}}</ref> |
|||
== Synthesis == |
|||
As mentioned before, ethionine is the ethyl-analogue of methionine. Because of this fact, the reactive properties of both compounds are very similar. For a long time, ethionine is thought to occur only in a man-made form. But in 1961 Fisher and Mallette found that ethionine occurs naturally in [[Escherichia coli]] and that the compound is synthesized biologically by the bacteria.<ref>Fisher JF, Mallette MF. 1961. The natural occurrence of ethionine in bacteria. The Journal of General Physiology. 45(1):1-13.</ref> |
|||
[[File:Methionine simple.png|left|thumb|234x234px|Chemical structure of methionine]] |
|||
== Metabolism == |
|||
Because of the relativity of ethionine to methionine, it is suggested that the metabolism of these two compounds is very similar. The enzymes involved in the metabolism of methionine are thought to be involved in the metabolism of ethionine too. The metabolism of ethionine in rats has been studied by Brada et al.<ref name=":2">Brada Z, Bulba S, Cohen J. 1975. The metabolism of ethionine in rats. Cancer Research. 35(10):2674-2683.</ref> They exposed rats to ethionine and found, as expected, large amounts of ethionine metabolites in the [[blood plasma]]. The distribution of ethionine was not entirely uniform as it appeared to persist longer in the [[kidney]]s than in several other examined organs. The measured concentration of ethionine metabolites in the [[small intestine]] seemed to be relatively low. The reason for this is suggested to be due to a quick transport of ethionine from the [[Gastrointestinal tract|intestinal mucosa]] into the [[Circulatory system|circulation]]. Brada et al have shown that the main ethionine metabolite in urine is ''N''-acetylethionine sulfoxide, after that ''S''-Adenosyl ethionine. And as third component, [[ethionine sulfoxide]] was found. Ethionine sulfoxide is unable to be activated to [[S-Adenosyl ethionine|''S''-Adenosyl ethionine]]. Thus ethionine sulfoxide depends on its reduction to ethionine to be biologically activated. Ethionine sulfoxide is able to be acetylated to ''N''-acetylethionine sulfoxide. This compound was detected in all examined organs by Brada et al. The formation of ''N-''acetylethionine is therefore considered to be a regular [[detoxification]] reaction as Brada et al state.<ref name=":2" /> |
|||
In the [[metabolic pathway]] of ethionine, first [[adenosine]] is added to ethionine just as adenosine is added to methionine in the pathway of methionine. From there [[S-Adenosyl-L-homocysteine|S-adenosyl homocysteine]] is formed. When S-adenosyl homocysteine is formed, it is broken down into [[homocysteine]] and [[adenosine]]. These metabolites are both reused again. The formation of S-adenosyl homocysteine is reduced when S-adenosyl ethionine is formed because it is effectively trapped as S-adenosyl ethionine. This will also result in less formation of adenosine and eventually in less formation of ATP. The shortage of ATP results in inhibition of protein synthesis. This can lead to disruption of metabolism.This shortage of ATP also indirectly causes accumulation of [[triglyceride]]s. This is a result of a deficiency in [[apolipoprotein]] complex production. This apolipoprotein complex is responsible for the transportation of triglycerides out of the liver.<ref name=":0" /> |
|||
[[File:Metabolism of methionine and ethionine (1).jpg|thumb|606x606px|Overview of the metabolic pathway of methionine and ethionine. The red arrow indicates the reduced formation of S-Adenosyl homocysteine in case of the ethionine pathway. Normally, S-Adenosyl homocysteine is processed into homocysteine and adenosine. Because of the reduced formation of S-adenosyl homocysteine, this influences the production of ATP.]] |
|||
== Mechanism of Action == |
|||
The most important change on biochemical level is the fast decline of available ATP. Furthermore there is a disturbance in the synthesis of impaired proteins, the incorporation of defective amino acids, and the appearance of [[RNA]] and proteins containing the ethyl rather than the methyl group. The concentration of [[cholesterol]], [[triglyceride]]s, [[phospholipid]], and [[lipoprotein]] in the plasma are all decreased. The mechanism of action on the carcinogenicity of ethionine is not completely known. However it is assumed that [[RNA synthesis]] or the production of abnormal ethylated [[nucleic acid]]s and hence disruption of [[Transcription (biology)|transcription]], [[Translation (biology)|translation]], or possibly [[DNA replication|replication]] is involved. The [[Ames test]] was found to be negative. However the metabolite of ethionine, homocysteine, is highly [[mutagen]]ic. This is the reason why ethionine is considered to be carcinogenic.<ref name=":0" /> |
|||
This assumption is justified when one looks at another metabolite of ethionine. When ethionine is activated into the energy rich S-adenosyl it can act as an ethyl donor. S-adenosyl can cause the ethylation of DNA and thereby confirm the carcinogenicity of ethionine.<ref name=":2" /> |
|||
== Efficacy == |
|||
Because of the high level of toxicity of ethionine, the compound is only used non medically. It has been tested on humans with advanced neoplasmatic disease. The research was eventually was stopped because of the extreme toxicity of ethionine. Because of this toxicity, ethionine its main (and only) use is to induce carcinoma (of the liver) in animal testing. |
|||
== Toxicity and effects on animals == |
|||
Ethionine has been studied upon micro-organisms as well as on higher animals. In one study tests were performed on humans. The toxicity of ethionine for humans was confirmed.<ref>White LP, Shimkin MB. 1954. Effects of dl-ethionine in six patients with neoplastic disease. Cancer. 7(5):867-872.</ref> |
|||
=== Acute effects === |
|||
After acute doses, ethionine causes [[fatty liver]], but prolonged administration results in [[Cirrhosis|liver cirrhosis]] and [[Hepatocellular carcinoma|hepatic carcinoma]]. A single dose of ethionine results in the accumulation of triglycerides in the [[Endoplasmic reticulum|endoplasmatic reticulum]] of the [[hepatocyte]]s close to the [[portal vein]]. A further accumulation results in the forming of fatty droplets in both cells close to the portal vein as cells further into the liver.<ref name=":0" /> |
|||
=== Chronic Effects === |
|||
Chronic administration leads to the proliferation of bile duct cells. Resulting in hepatocyte atrophy, fibrous tissue surrounding proliferated bile ducts. This eventually leads to cirrhosis, hepatocellular carcinoma, and [[necrosis]].<ref name=":0" /> Other studies show that other organs can be affected, organs such as the [[pancreas]], [[kidney]] and [[testis]].<ref name=":1" /> |
|||
Ethionine is considered to be a highly toxic compound. A longer exposure to ethionine results in certain death. |
|||
==References== |
==References== |
||
{{Reflist}} |
|||
<references /> |
|||
[[Category:Carcinogens]] |
[[Category:Carcinogens]] |
||
[[Category:Sulfur amino acids]] |
[[Category:Sulfur amino acids]] |
||
[[Category:Thioethers]] |
[[Category:Thioethers]] |
||
{{amine-stub}} |
|||
Revision as of 02:47, 26 October 2017
| |
| Names | |
|---|---|
| IUPAC name
2-Amino-4-ethylsulfanylbutyric acid
| |
| Other names
S-Ethyl-L-homocysteine
| |
| Identifiers | |
3D model (JSmol)
|
|
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.000.588 |
PubChem CID
|
|
CompTox Dashboard (EPA)
|
|
| |
| |
| Properties | |
| C6H13NO2S | |
| Molar mass | 163.239 g/mol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
Ethionine is a non-proteinogenic amino acid structurally related to methionine, with an ethyl group in place of the methyl group.
Ethionine is an antimetabolite and methionine antagonist. It prevents amino acid incorporation into proteins and interferes with cellular use of adenosine triphosphate (ATP). Because of these pharmacological effects, ethionine is highly toxic and is a potent carcinogen.[1]
References
- ^ Narayan Shivapurkar, Mary J. Wilson and Lionel A. Poirier (1984). "Hypomethylation of DNA in ethionine-fed rats". Carcinogenesis. 5 (8): 989–992. doi:10.1093/carcin/5.8.989. PMID 6744518.
 | This article about an amine is a stub. You can help Wikipedia by expanding it. |