Ethionine

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Ethionine
Ethionine.png
Names
IUPAC name
2-Amino-4-ethylsulfanylbutyric acid
Other names
S-Ethyl-L-homocysteine
Identifiers
3D model (Jmol)
ChEBI
ChemSpider
ECHA InfoCard 100.032.682
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).
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Infobox references

Ethionine is an analogue of the essential amino acid methionine. It has an 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 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.[1] However, when continuously administered, ethionine is lethal.

History[edit]

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.[2] Harris and Kohn (1941) observed growth inhibition by ethionine within E. Coli, this could also be counteracted with methionine.[3] Throughout the following years more and more research was done to prove the toxicity, carcinogenicity and pathology of ethionine.[4]

Chemical structure of ethionine

Synthesis[edit]

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. [5]

Chemical structure of methionine

Metabolism[edit]

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.[6] 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 kidneys 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 intestinal mucosa into the 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. 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.[6]

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 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 triglycerides. 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.[1]

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[edit]

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, triglycerides,  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 acids and hence disruption of transcription, translation, or possibly replication is involved. The Ames test was found to be negative. However the metabolite of ethionine, homocysteine, is highly mutagenic. This is the reason why ethionine is considered to be carcinogenic.[1]

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.[6]

Efficacy[edit]

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[edit]

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.[7]

Acute effects[edit]

After acute doses, ethionine causes fatty liver, but prolonged administration results in liver cirrhosis and hepatic carcinoma. A single dose of ethionine results in the accumulation of triglycerides in the endoplasmatic reticulum of the hepatocytes 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.[1]

Chronic Effects[edit]

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.[1] Other studies show that other organs can be affected, organs such as the pancreas, kidney and testis.[4]

Ethionine is considered to be a highly toxic compound. A longer exposure to ethionine results in certain death.

References[edit]

  1. ^ a b c d e Timbrell JA. 2008. Biochemical mechanisms of toxicity. Principles of biochemical toxicology, fourth edition. CRC Press. p. 293-407.
  2. ^ Du Vigneaud V. 1941. Interrelationships between choline and other methylated compounds. Biol Symposia.
  3. ^ 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.
  4. ^ a b Farber E. 1963. Ethionine carcinogenesis*†. In: Alexander H, Sidney W, editors. Advances in cancer research. Academic Press. p. 383-474.
  5. ^ Fisher JF, Mallette MF. 1961. The natural occurrence of ethionine in bacteria. The Journal of General Physiology. 45(1):1-13.
  6. ^ a b c Brada Z, Bulba S, Cohen J. 1975. The metabolism of ethionine in rats. Cancer Research. 35(10):2674-2683.
  7. ^ White LP, Shimkin MB. 1954. Effects of dl-ethionine in six patients with neoplastic disease. Cancer. 7(5):867-872.