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Emetine is a drug used as both an anti-protozoal and to induce vomiting. It is produced from the ipecac root.

Early emetine-based preparations

Early use of emetine was in the form of oral administration of the extract of ipecac root, or ipecacuanha. This extract was originally thought to contain only one alkaloid, emetine, but was found to contain several, including cephaeline, psychotrine and others. Although this therapy was reportedly successful, the extract caused vomiting in many patients which reduced its utility. In some cases, it was given with opioids to reduce nausea. Other suggestions to reduce nausea involved coating the drug to allow it to be released after digestion in the stomach. ^[1]

Use of emetine as anti-amoebic

The identification of emetine as a more potent agent improved the treatment of amoebiasis. While use of emetine still caused nausea, it was more effective than the crude extract of ipecac root. Additionally, emetine could be administered hypodermically which still produced nausea, but not to the degree experienced in oral administration.

Although it is a potent antiprotozoal, the drug also can interfere with muscle contractions, leading to cardiac failure in some cases. Because of this, in some uses it is required to be administered in a hospital so that adverse events can be addressed.

Dehydroemetine

Dehydroemetine is a synthetically produced antiprotozoal agent similar to emetine in its anti-amoebic properties and structure (they differ only in a double bond next to the ethyl group), but it produces fewer side effects.

Cephaeline

Cephaeline is a desmethyl analog of emetine also found in ipecac root.

Use in blocking protein synthesis

Emetine dihydrochloro hydrate is used in the laboratory to block protein synthesis in eukaryotic cells. It does this by binding to the 40S subunit of the ribosome.^[2] This can thus be used in the study of protein degradation in cells. Mutants resistant to emetine are altered in the 40S ribosomal subunit (S14 protein),^[3]^[4] and they exhibit cross-resistance to cryptopleurine, tylocrebrine, cephaeline and tubulosine, but not other inhibitors of protein synthesis.^[5] The compounds to which these mutants exhibit cross-resistance have been shown to share common structural determinants with emetine that are responsible for their biological activities.^[6]

Biosynthesis

Proposed biosynthesis of emetine

The biosynthesis of cephaeline and emetine come from two main biosynthesis pathways: the biosynthesis of Dopamine from L-tyrosine and the biosynthesis of secologanin from geranyl diphosphate. Biosynthesis begins from the reaction between dopamine and secologanin forming N-deacetylisoipecoside (S-form) and N-deacetylipecoside (R-form). The S-form then goes through a Pictet-Spengler type reaction followed by a series of O-methylations and the removal of glucose, with O-methyltransferases and a glycosidase, to form proemetine. Proemetine then reacts with another dopamine molecule to form 7'-O-demethylcephaeline. The final products are then produced with a 7'-O-methylation to make cephaeline and a 6'-O-methylation successively to make emetine.^[7]^[8]

Side effects

Heavy or overusage of emetine can carry the risk of developing proximal myopathy and/or cardiomyopathy.

References

^ Cushny, Arthur Robertson (1918). A Textbook of pharmacology and therapeutics, or the action of drugs in health and disease. Lea and Febiger, New York. pp. 438–442.
^ (Jimenez et al., Enzymatic and nonenzymatic translocation of yeast polysomes. Site of action of a number of inhibitors. Biochemistry, 1977 16;4727-4730)
^ Gupta, R.S. and Siminovitch. L. (1977). The molecular basis of emetine resistance in Chinese hamster ovary cells: Alteration in the 40S ribosomal subunit. Cell 10: 61-66.
^ Rhoads, D. D. and Roufa, D. J. (1985) Emetine resistance of Chinese hamster cells: structures of wild-type and mutant ribosomal protein S14 mRNAs Mol. Cell. Biol. 5:1655-1659.
^ Gupta, R.S. and Siminovitch, L. (1977). Mutants of CHO cells resistant to the protein synthesis inhibitors, cryptopleurine and tylocrebrine: Genetic and structural evidence for common site of action of emetine, cryptopleurine, tylocrebrine and tubulosine. Biochemistry 16: 3209-3214.
^ Gupta, R.S., Krepinsky, G.H. and Siminovitch, L. (1980). Structural determinants responsible for the biological activity of emetine, cryptopleurine and tylocrebrine: Structure-activity relationship among related compounds. Mol. Pharmacol. 18: 136-143.
^ Cheong, BE; Takemura, T; Yoshimatsu, K; Sato, F (2011). "Molecular cloning of an O-methyltransferase from adventitious roots of Carapichea ipecacuanha.". Bioscience, Biotechnology, and Biochemistry 75 (1): 107–13. doi:10.1271/bbb.100605. PMID 21228475.
^ Nomura, T; Kutchan, TM (2010-03-05). "Three New O-Methyltransferases Are Sufficient for All O-Methylation Reactions of Ipecac Alkaloid Biosynthesis in Root Culture of Psychotria ipecacuanha". The Journal of Biological Chemistry 285 (10): 7722–38. doi:10.1074/jbc.M109.086157. PMC 2844217. PMID 20061395.

UpToDate Contents

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English Journal

Emetine enhances the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of pancreatic cancer cells by downregulation of myeloid cell leukemia sequence-1 protein.

Han Y, Park S, Kinyua AW, Andera L, Kim KW, Kim I.Author information Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.AbstractAlthough the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, it shows limited efficacy in human pancreatic cancer cells. Protein synthesis inhibition has been reported to sensitize cancer cells to apoptosis-inducing agents, but the detailed mechanism by which protein synthesis inhibition sensitize cells to TRAIL has not been determined. To investigate the mechanism underlying pancreatic cancer cell resistance to TRAIL, we performed a small scale high-throughput compound screening in AsPC-1 pancreatic cancer cells using a bioactive small molecule library. We identified 8 compounds that reproducibly sensitize AsPC-1 cells to TRAIL-induced apoptosis. One of these compounds, emetine hydrochloride, when combined with subtoxic concentrations of TRAIL, induced massive apoptosis in AsPC-1 and BxPC-3 pancreatic cancer cells. Cell death analysis revealed that the sensitizing effects of emetine were specific to TRAIL. Emetine downregulated the expression of the TRAIL-related anti-apoptotic protein Mcl-1 in a dose- and time-dependent manner. Furthermore, specific knockdown of Mcl-1 using small interfering RNA without emetine treatment sensitized pancreatic cancer cells to TRAIL. Emetine sensitization of pancreatic cancer cells to TRAIL via Mcl-1 was confirmed under hypoxic conditions. Taken together, these findings strongly suggest that Mcl-1 is involved in pancreatic cancer cell resistance to TRAIL, and emetine facilitates the apoptosis of TRAIL-tolerant pancreatic cancer cells by specifically inhibiting Mcl-1 function.
Oncology reports.Oncol Rep.2014 Jan;31(1):456-62. doi: 10.3892/or.2013.2838. Epub 2013 Nov 7.
Although the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent, it shows limited efficacy in human pancreatic cancer cells. Protein synthesis inhibition has been reported to sensitize cancer cells to apoptosis-inducing agents, but the detailed me
PMID 24213797

The synthesis and structure revision of NSC-134754.

Hickin JA, Ahmed A, Fucke K, Ashcroft M, Jones K.Author information CRUK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK. keith.jones@icr.ac.uk.AbstractThe synthesis of emetine analogue NSC-134754, a potent inhibitor of the HIF pathway, has been accomplished and its structure reassigned. The stereochemistry of NSC-134754 has been assigned for the first time using X-ray crystallography and it has been demonstrated that only one diastereoisomer is active against HIF.
Chemical communications (Cambridge, England).Chem Commun (Camb).2013 Dec 16. [Epub ahead of print]
The synthesis of emetine analogue NSC-134754, a potent inhibitor of the HIF pathway, has been accomplished and its structure reassigned. The stereochemistry of NSC-134754 has been assigned for the first time using X-ray crystallography and it has been demonstrated that only one diastereoisomer is ac
PMID 24336320

Different routes lead to apoptosis in unfertilized sea urchin eggs.

Philippe L, Tosca L, Zhang WL, Piquemal M, Ciapa B.Author information Centre de Neurosciences Paris-Sud (CNPS), CNRS UMR 8195 Université Paris XI, Bât. 444, 91405, Orsay Cedex, France.AbstractResults obtained in various species, from mammals to invertebrates, show that arrest in the cell cycle of mature oocytes is due to a high ERK activity. Apoptosis is stimulated in these oocytes if fertilization does not occur. Our previous data suggest that apoptosis of unfertilized sea urchin eggs is the consequence of an aberrant short attempt of development that occurs if ERK is inactivated. They contradict those obtained in starfish, another echinoderm, where inactivation of ERK delays apoptosis of aging mature oocytes that are nevertheless arrested at G1 of the cell cycle as in the sea urchin. This suggests that the cell death pathway that can be activated in unfertilized eggs is not the same in sea urchin and in starfish. In the present study, we find that protein synthesis is necessary for the survival of unfertilized sea urchin eggs, contrary to starfish. We also compare the effects induced by Emetine, an inhibitor of protein synthesis, with those triggered by Staurosporine, a non specific inhibitor of protein kinase that is widely used to induce apoptosis in many types of cells. Our results indicate that the unfertilized sea urchin egg contain different mechanisms capable of leading to apoptosis and that rely or not on changes in ERK activity, acidity of intracellular organelles or intracellular Ca and pH. We discuss the validity of some methods to investigate cell death such as measurements of caspase activation with the fluorescent caspase indicator FITC-VAD-fmk or acidification of intracellular organelles, methods that may lead to erroneous conclusions at least in the sea urchin model.
Apoptosis : an international journal on programmed cell death.Apoptosis.2013 Dec 13. [Epub ahead of print]
Results obtained in various species, from mammals to invertebrates, show that arrest in the cell cycle of mature oocytes is due to a high ERK activity. Apoptosis is stimulated in these oocytes if fertilization does not occur. Our previous data suggest that apoptosis of unfertilized sea urchin eggs i
PMID 24337868

Japanese Journal

Selective determination method for measurement of methylmercury and ethylmercury in soil/sediment samples using high-performance liquid chromatography–chemiluminescence detection coupled with simple extraction technique

KODAMATANI Hitoshi,TOMIYASU Takashi,コダマタニヒトシ,トミヤスタカシ,児玉谷仁,冨安卓滋
Journal of Chromatography A 1288, 155-159, 2013-05-03
… Finally, an emetine-dithiocarbamate (emetineCS2) solution is added to the EDTA solution to form emetineCS2–alkylmercury complexes. …
NAID 120005303692

Molecular Cloning of an O-Methyltransferase from Adventitious Roots of Carapichea ipecacuanha

Cheong Bo Eng,Takemura Tomoya,Yoshimatsu Kayo [他],SATO Fumihiko
Bioscience, biotechnology, and biochemistry 75(1), 107-113, 2011-01-23
… Carapichea ipecacuanha produces various emetine-type alkaloids, known as ipecac alkaloids, which have long been used as expectorants, emetics, and amebicides. … The encoded protein (CiOMT1) showed 98% sequence identity to IpeOMT2, which catalyzes the 7′-O-methylation of 7′-O-demethylcephaeline to form cephaeline at the penultimate step of emetine biosynthesis (Nomura and Kutchan, J. …
NAID 10027896875

Effect of emetine, a protein synthesis inhibitor, on larval tail resorption in the ascidian Halocynthia roretzi

Matsumura Kiyotaka,Nagano Manami,Tsukamoto Sachiko [他],KATO Haruko,FUSETANI Nobuhiro
Sessile organisms 23(2), 43-46, 2006-08-25
NAID 10018254289

Related Pictures

★リンクテーブル★

リンク元	「エメチン」
拡張検索	「desmethylemetine」
関連記事	「emetin」

「エメチン」

Emetine
Systematic (IUPAC) name
	(2S,3R,11bS)-2-{[(1R)-6,7-Dimethoxy-1,2,3,4-; tetrahydroisoquinolin-1-yl]methyl}-3-ethyl-9,10-; dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido; [2,1-a]isoquinoline
Clinical data
AHFS/Drugs.com	International Drug Names
Identifiers
CAS Registry Number	483-18-1
ATC code	P01AX02 QP51AX02
PubChem	CID: 10219
ChemSpider	9802
UNII	X8D5EPO80M
KEGG	C09421
ChEBI	CHEBI:4781
ChEMBL	CHEMBL50588
Chemical data
Formula	C29H40N2O4
Molecular mass	480.639 g/mol
	SMILES O(c1cc2c(cc1OC)[C@H](NCC2)C[C@H]5C[C@H]4c3c(cc(OC)c(OC)c3)CCN4C[C@@H]5CC)C ;
	InChI InChI=1S/C29H40N2O4/c1-6-18-17-31-10-8-20-14-27(33-3)29(35-5)16-23(20)25(31)12-21(18)11-24-22-15-28(34-4)26(32-2)13-19(22)7-9-30-24/h13-16,18,21,24-25,30H,6-12,17H2,1-5H3/t18-,21-,24+,25-/m0/s1 ; Key:AUVVAXYIELKVAI-CKBKHPSWSA-N ;
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