Editing Ricin

{{Short description|Type of toxic lectin}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Use dmy dates|date=May 2020}}
{{Infobox nonhuman protein
| Name = Ricin
| image = ricin structure.png
| width = 
| caption = Ricin structure ({{PDB|2AAI}}). The '''A''' chain is shown in blue and the '''B''' chain in orange.
| Organism = ''Ricinus communis''
| TaxID = 3988
| Symbol = RCOM_2159910
| AltSymbols = 
| IUPHAR_id = 
| ATC_prefix = 
| ATC_suffix = 
| ATC_supplemental = 
| CAS_number = 
| CAS_supplemental = 
| DrugBank = 
| EntrezGene = 8287993
| RefSeqmRNA = XM_002534603.1
| RefSeqProtein = XP_002534649.1
| UniProt = P02879
| ECnumber = 3.2.2.22
| Chromosome = whole genome
| EntrezChromosome = NW_002995687.1
| GenLoc_start = 3835
| GenLoc_end = 6287
}}
{{Infobox protein family
| Symbol = RIP
| Name = Ribosome-inactivating protein (Ricin A chain)
| image = 
| width =
| caption = 
| Pfam = PF00161
| Pfam_clan =
| InterPro = IPR001574
| SMART =
| PROSITE = PDOC00248
| MEROPS =
| SCOP = 1paf
| TCDB =
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
{{Infobox protein family
| Symbol = N/A
| Name = Ricin-type beta-trefoil lectin domain (Ricin B chain)
| image =
| width =
| caption =
| Pfam = PF00652
| Pfam_clan = CL0066
| InterPro =
| SMART =
| PROSITE = IPR000772
| MEROPS =
| SCOP = 1abr
| TCDB =
| OPM family =
| OPM protein =
| CAZy = CBM13
| CDD = cd00161
}}

'''Ricin''' ({{IPAc-en|ˈ|r|aɪ|s|ɪ|n}} {{respell|RY|sin}}) is a [[lectin]] (a carbohydrate-binding [[protein]]) and a highly potent [[toxin]] produced in the seeds of the [[castor oil plant]], ''Ricinus communis''. The [[median lethal dose]] (LD<sub>50</sub>) of ricin for mice is around 22 [[micrograms]] per kilogram of body weight via [[intraperitoneal]] injection. Oral exposure to ricin is far less toxic. An estimated lethal oral dose in humans is approximately one milligram per kilogram of body weight.<ref name="Efsa.europa.eu">{{cite journal | publisher = European Food Safety Authority | title = Ricin (from Ricinus communis) as undesirable substances in animal feed-Scientific Opinion of the Panel on Contaminants in the Food Chain. | journal = EFSA Journal | date = September 2008 | volume = 6 | issue = 9 | pages = 726 |doi=10.2903/j.efsa.2008.726 |doi-access= }}</ref>

Ricin is a [[toxalbumin]] and was first described by [[Peter Hermann Stillmark]], the founder of [[lectin]]ology. Ricin is chemically similar to [[Robin (toxin)|robin]].

== Biochemistry ==
Ricin is classified as a type 2 [[ribosome-inactivating protein]] (RIP). Whereas type 1 RIPs are composed of a single protein chain that possesses catalytic activity, type 2 RIPs, also known as holotoxins, are composed of two different protein chains that form a [[heterodimeric]] complex. Type 2 RIPs consist of an A chain that is functionally equivalent to a type 1 RIP, covalently connected by a single [[disulfide bond]] to a B chain that is catalytically inactive, but serves to mediate transport of the A-B protein complex from the cell surface, via vesicle carriers, to the lumen of the [[endoplasmic reticulum]] (ER). Both type 1 and type 2 RIPs are functionally active against ribosomes ''in vitro''; however, only type 2 RIPs display [[cytotoxicity]] due to the [[lectin]]-like properties of the B chain. To display its ribosome-inactivating function, the ricin disulfide bond must be [[redox|reductively]] cleaved.<ref name="pmid3606124">{{cite journal | vauthors = Wright HT, Robertus JD | title = The intersubunit disulfide bridge of ricin is essential for cytotoxicity | journal = Archives of Biochemistry and Biophysics | volume = 256 | issue = 1 | pages = 280–284 | date = July 1987 | pmid = 3606124 | doi = 10.1016/0003-9861(87)90447-4 }}</ref>

=== Biosynthesis ===
Ricin is [[Protein biosynthesis|synthesized]] in the [[endosperm]] of castor oil plant seeds.<ref name="Lord_Roberts_2005">{{cite book |veditors=Raffael S, Schmitt M | title = Microbial Protein Toxins | series = Topics in Current Genetics | volume = 11 | publisher = Springer | location = Berlin | year = 2005 | pages = 215–233 | isbn = 978-3-540-23562-0 |vauthors=Lord MJ, Roberts LM | chapter = Ricin: structure, synthesis, and mode of action | doi = 10.1007/b100198 }}</ref> The ricin [[protein precursor|precursor protein]] is 576 [[amino acid residue]]s in length and contains a [[signal peptide]] (residues 1–35), the ricin A chain (36–302), a linker peptide (303–314), and the ricin B chain (315–576).<ref name="urlRicin precursor - Ricinus communis (Castor bean)">{{cite web | url = https://www.uniprot.org/uniprot/P02879 | title = P02879 Ricin precursor – Ricinus communis (Castor bean) | publisher = UniProt Consortium | work = UniProtKB}}</ref> The [[N-terminal]] signal sequence delivers the prepropolypeptide to the [[endoplasmic reticulum]] (ER) and then the signal peptide is cleaved off. Within the [[lumen (anatomy)|lumen]] of the ER the propolypeptide is [[glycosylated]] and a [[protein disulfide isomerase]] catalyzes [[disulfide bond]] formation between [[cysteine]]s 294 and 318. The propolypeptide is further glycosylated within the [[Golgi apparatus]] and transported to protein storage bodies. The propolypeptide is cleaved within protein bodies by an [[endopeptidase]] to produce the mature ricin protein that is composed of a 267 residue A chain and a 262 residue B chain that are covalently linked by a single disulfide bond.<ref name="Lord_Roberts_2005"/>

=== Structure ===
In terms of structure, ricin closely resembles abrin-a, an isomer of [[abrin]]. The [[Protein quaternary structure|quaternary structure]] of ricin is a globular, glycosylated heterodimer of approximately 60–65 [[Dalton (unit)|kDa]].<ref name="pmid4730499"/> Ricin toxin A chain and ricin toxin B chain are of similar molecular weights, approximately 32 kDa and 34 kDa, respectively.[[File:Alignment Abrin Ricin.png|thumb|A comparison of the similar structures of abrin-a (red) and ricin (blue)|alt=|left]]
* '''Ricin toxin A chain''' (RTA) is an ''N''-[[glycoside hydrolase]] composed of 267 amino acids.<ref name="pmid4730499">{{cite journal | vauthors = Olsnes S, Pihl A | title = Different biological properties of the two constituent peptide chains of ricin, a toxic protein inhibiting protein synthesis | journal = Biochemistry | volume = 12 | issue = 16 | pages = 3121–3126 | date = July 1973 | pmid = 4730499 | doi = 10.1021/bi00740a028 }}</ref> It has three structural domains with approximately 50% of the [[polypeptide]] arranged into [[alpha-helix|alpha-helices]] and [[beta-sheet]]s.<ref name="pmid7990130">{{cite journal | vauthors = Weston SA, Tucker AD, Thatcher DR, Derbyshire DJ, Pauptit RA | title = X-ray structure of recombinant ricin A-chain at 1.8 A resolution | journal = Journal of Molecular Biology | volume = 244 | issue = 4 | pages = 410–422 | date = December 1994 | pmid = 7990130 | doi = 10.1006/jmbi.1994.1739 }}</ref> The three domains form a pronounced cleft that is the active site of RTA.
* '''Ricin toxin B chain''' (RTB) is a [[lectin]] composed of 262 amino acids that is able to bind terminal [[galactose]] residues on cell surfaces.<ref name="pmid1717462">{{cite journal | vauthors = Wales R, Richardson PT, Roberts LM, Woodland HR, Lord JM | title = Mutational analysis of the galactose binding ability of recombinant ricin B chain | journal = The Journal of Biological Chemistry | volume = 266 | issue = 29 | pages = 19172–19179 | date = October 1991 | pmid = 1717462 | doi = 10.1016/S0021-9258(18)54978-4 | doi-access = free }}</ref> RTB forms a bilobal, barbell-like structure lacking [[alpha helix|alpha-helices]] or [[beta sheet|beta-sheets]] where individual lobes contain three [[protein domain|subdomains]]. At least one of these three subdomains in each homologous lobe possesses a sugar-binding pocket that gives RTB its functional character.
While other plants contain the protein chains found in ricin, both protein chains must be present to produce toxic effects. For example, plants that contain only protein chain A, such as [[barley]], are not toxic because without the link to protein chain B, protein chain A cannot enter the cell and do damage to ribosomes.<ref name="Harkup-2015">{{Cite book|title = A is For Arsenic: The poisons of Agatha Christie| author = [[Kathryn Harkup]] |publisher = Bloomsbury Sigma|year = 2015|isbn = 978-1-4729-1130-8|location = London|pages = [https://archive.org/details/isforarsenicpois0000hark/page/222 222–236]|url = https://archive.org/details/isforarsenicpois0000hark/page/222}}</ref>

=== Entry into the cytoplasm ===
Ricin B chain binds complex carbohydrates on the surface of [[eukaryotic]] cells containing either terminal [[N-acetylgalactosamine|''N''-acetylgalactosamine]] or beta-1,4-linked galactose residues. In addition, the [[mannose]]-type [[glycan]]s of ricin are able to bind to cells that express [[mannose receptor]]s.<ref name="pmid8453986">{{cite journal | vauthors = Magnusson S, Kjeken R, Berg T | title = Characterization of two distinct pathways of endocytosis of ricin by rat liver endothelial cells | journal = Experimental Cell Research | volume = 205 | issue = 1 | pages = 118–125 | date = March 1993 | pmid = 8453986 | doi = 10.1006/excr.1993.1065 }}</ref> RTB has been shown to bind to the cell surface on the order of 10<sup>6</sup>–10<sup>8</sup> ricin molecules per cell surface.<ref name="pmid7657599">{{cite journal | vauthors = Sphyris N, Lord JM, Wales R, Roberts LM | title = Mutational analysis of the Ricinus lectin B-chains. Galactose-binding ability of the 2 gamma subdomain of Ricinus communis agglutinin B-chain | journal = The Journal of Biological Chemistry | volume = 270 | issue = 35 | pages = 20292–20297 | date = September 1995 | pmid = 7657599 | doi = 10.1074/jbc.270.35.20292 | doi-access = free }}</ref>

The profuse binding of ricin to surface membranes allows internalization with all types of membrane [[invagination]]s. The holotoxin can be taken up by [[clathrin]]-coated pits, as well as by clathrin-independent pathways including [[caveolae]] and [[macropinocytosis]].<ref name="pmid2862151">{{cite journal | vauthors = Moya M, Dautry-Varsat A, Goud B, Louvard D, Boquet P | title = Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diphtheria toxin but not that of ricin toxin | journal = The Journal of Cell Biology | volume = 101 | issue = 2 | pages = 548–559 | date = August 1985 | pmid = 2862151 | pmc = 2113662 | doi = 10.1083/jcb.101.2.548 }}</ref><ref name="pmid11567873">{{cite journal | vauthors = Nichols BJ, Lippincott-Schwartz J | title = Endocytosis without clathrin coats | journal = Trends in Cell Biology | volume = 11 | issue = 10 | pages = 406–412 | date = October 2001 | pmid = 11567873 | doi = 10.1016/S0962-8924(01)02107-9 }}</ref> Intracellular [[vesicle (biology)|vesicles]] shuttle ricin to [[endosome]]s that are delivered to the [[Golgi apparatus]]. The active acidification of endosomes is thought to have little effect on the functional properties of ricin. Because ricin is stable over a wide pH range, degradation in endosomes or [[lysosome]]s offers little or no protection against ricin.<ref name="pmid14579547">{{cite journal | vauthors = Lord MJ, Jolliffe NA, Marsden CJ, Pateman CS, Smith DC, Spooner RA, Watson PD, Roberts LM | title = Ricin. Mechanisms of cytotoxicity | journal = Toxicological Reviews | volume = 22 | issue = 1 | pages = 53–64 | year = 2003 | pmid = 14579547 | doi = 10.2165/00139709-200322010-00006 }}</ref> Ricin molecules are thought to follow [[retrograde transport]] via early endosomes, the trans-Golgi network, and the Golgi to enter the [[Lumen (anatomy)|lumen]] of the [[endoplasmic reticulum]] (ER).<ref name="pmid16603059">{{cite journal | vauthors = Spooner RA, Smith DC, Easton AJ, Roberts LM, Lord JM | title = Retrograde transport pathways utilised by viruses and protein toxins | journal = Virology Journal | volume = 3 | pages = 26 | date = April 2006 | pmid = 16603059 | pmc = 1524934 | doi = 10.1186/1743-422X-3-26 | doi-access = free }}</ref>

For ricin to function cytotoxically, RTA must be reductively cleaved from RTB to release a [[steric]] block of the RTA active site. This process is catalysed by the protein PDI ([[protein disulphide isomerase]]) that resides in the lumen of the ER.<ref name="pmid15225124">{{cite journal | vauthors = Spooner RA, Watson PD, Marsden CJ, Smith DC, Moore KA, Cook JP, Lord JM, Roberts LM | title = Protein disulphide-isomerase reduces ricin to its A and B chains in the endoplasmic reticulum | journal = The Biochemical Journal | volume = 383 | issue = Pt 2 | pages = 285–293 | date = October 2004 | pmid = 15225124 | pmc = 1134069 | doi = 10.1042/BJ20040742 }}</ref><ref name="pmid15081871">{{cite journal | vauthors = Bellisola G, Fracasso G, Ippoliti R, Menestrina G, Rosén A, Soldà S, Udali S, Tomazzolli R, Tridente G, Colombatti M | title = Reductive activation of ricin and ricin A-chain immunotoxins by protein disulfide isomerase and thioredoxin reductase | journal = Biochemical Pharmacology | volume = 67 | issue = 9 | pages = 1721–1731 | date = May 2004 | pmid = 15081871 | doi = 10.1016/j.bcp.2004.01.013 }}</ref> Free RTA in the ER lumen then partially unfolds and partially buries into the ER membrane, where it is thought to mimic a misfolded membrane-associated protein.<ref name="pmid19211561">{{cite journal | vauthors = Mayerhofer PU, Cook JP, Wahlman J, Pinheiro TT, Moore KA, Lord JM, Johnson AE, Roberts LM | title = Ricin A chain insertion into endoplasmic reticulum membranes is triggered by a temperature increase to 37 {degrees}C | journal = The Journal of Biological Chemistry | volume = 284 | issue = 15 | pages = 10232–10242 | date = April 2009 | pmid = 19211561 | pmc = 2665077 | doi = 10.1074/jbc.M808387200 | doi-access = free }}</ref> Roles for the ER chaperones [[GRP94]],<ref name="Spooner">{{cite journal | vauthors = Spooner RA, Hart PJ, Cook JP, Pietroni P, Rogon C, Höhfeld J, Roberts LM, Lord JM | title = Cytosolic chaperones influence the fate of a toxin dislocated from the endoplasmic reticulum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 45 | pages = 17408–17413 | date = November 2008 | pmid = 18988734 | pmc = 2580750 | doi = 10.1073/pnas.0809013105 | doi-access = free | bibcode = 2008PNAS..10517408S | jstor = 25465291 }}</ref> [[EDEM1|EDEM]]<ref name="pmid16452630">{{cite journal | vauthors = Slominska-Wojewodzka M, Gregers TF, Wälchli S, Sandvig K | title = EDEM is involved in retrotranslocation of ricin from the endoplasmic reticulum to the cytosol | journal = Molecular Biology of the Cell | volume = 17 | issue = 4 | pages = 1664–1675 | date = April 2006 | pmid = 16452630 | pmc = 1415288 | doi = 10.1091/mbc.E05-10-0961 }}</ref> and [[Binding immunoglobulin protein|BiP]]<ref name="pmid23666197">{{cite journal | vauthors = Gregers TF, Skånland SS, Wälchli S, Bakke O, Sandvig K | title = BiP negatively affects ricin transport | journal = Toxins | volume = 5 | issue = 5 | pages = 969–982 | date = May 2013 | pmid = 23666197 | pmc = 3709273 | doi = 10.3390/toxins5050969 | doi-access = free }}</ref> have been proposed prior to the 'dislocation' of RTA from the ER lumen to the cytosol in a manner that uses components of the endoplasmic reticulum-associated protein degradation ([[ERAD]]) pathway. ERAD normally removes misfolded ER proteins to the cytosol for their destruction by cytosolic proteasomes. Dislocation of RTA requires ER membrane-integral E3 [[ubiquitin ligase]] complexes,<ref name="pmid20519439">{{cite journal | vauthors = Li S, Spooner RA, Allen SC, Guise CP, Ladds G, Schnöder T, Schmitt MJ, Lord JM, Roberts LM | title = Folding-competent and folding-defective forms of ricin A chain have different fates after retrotranslocation from the endoplasmic reticulum | journal = Molecular Biology of the Cell | volume = 21 | issue = 15 | pages = 2543–2554 | date = August 2010 | pmid = 20519439 | pmc = 2912342 | doi = 10.1091/mbc.E09-08-0743 }}</ref> but RTA avoids the [[ubiquitination]] that usually occurs with ERAD substrates because of its low content of [[lysine]] residues, which are the usual attachment sites for [[ubiquitin]].<ref name="pmid11876649">{{cite journal | vauthors = Deeks ED, Cook JP, Day PJ, Smith DC, Roberts LM, Lord JM | title = The low lysine content of ricin A chain reduces the risk of proteolytic degradation after translocation from the endoplasmic reticulum to the cytosol | journal = Biochemistry | volume = 41 | issue = 10 | pages = 3405–3413 | date = March 2002 | pmid = 11876649 | doi = 10.1021/bi011580v }}</ref> Thus, RTA avoids the usual fate of dislocated proteins (destruction that is mediated by targeting ubiquitinylated proteins to the cytosolic proteasomes). In the mammalian cell cytosol, RTA then undergoes triage by the cytosolic molecular chaperones [[Hsc70]] and [[Hsp90]] and their co-chaperones, as well as by one subunit (RPT5) of the [[proteasome]] itself, that results in its folding to a catalytic conformation,<ref name="Spooner" /><ref name="pmid23617410">{{cite journal | vauthors = Pietroni P, Vasisht N, Cook JP, Roberts DM, Lord JM, Hartmann-Petersen R, Roberts LM, Spooner RA | title = The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain | journal = The Biochemical Journal | volume = 453 | issue = 3 | pages = 435–445 | date = August 2013 | pmid = 23617410 | pmc = 3778710 | doi = 10.1042/BJ20130133 }}</ref> which de-purinates [[ribosome]]s, thus halting protein synthesis.

=== Ribosome inactivation ===
RTA has [[rRNA N-glycosylase|rRNA ''N''-glycosylase]] activity that is responsible for the cleavage of a [[glycosidic bond]] within the large [[ribosomal RNA|rRNA]] of the [[60S]] subunit of eukaryotic ribosomes.<ref name="pmid3036799">{{cite journal | vauthors = Endo Y, Tsurugi K | title = RNA N-glycosidase activity of ricin A-chain. Mechanism of action of the toxic lectin ricin on eukaryotic ribosomes | journal = The Journal of Biological Chemistry | volume = 262 | issue = 17 | pages = 8128–8130 | date = June 1987 | pmid = 3036799 | doi = 10.1016/S0021-9258(18)47538-2 | doi-access = free }}</ref> RTA specifically and irreversibly [[hydrolyses]] the ''N''-glycosidic bond of the [[adenine]] residue at position 4324 (A4324) within the [[28S ribosomal RNA|28S]] rRNA, but leaves the [[phosphodiester]] backbone of the RNA intact.<ref name="pmid3288622">{{cite journal | vauthors = Endo Y, Tsurugi K | title = The RNA N-glycosidase activity of ricin A-chain. The characteristics of the enzymatic activity of ricin A-chain with ribosomes and with rRNA | journal = The Journal of Biological Chemistry | volume = 263 | issue = 18 | pages = 8735–8739 | date = June 1988 | pmid = 3288622 | doi = 10.1016/S0021-9258(18)68367-X | doi-access = free }}</ref> The ricin targets A4324 that is contained in a highly [[conserved sequence]] of 12 [[nucleotide]]s universally found in eukaryotic ribosomes. The sequence, 5'-AGUACGAGAGGA-3', termed the sarcin-ricin loop, is important in binding [[elongation factor]]s during protein synthesis.<ref name="pmid4360718">{{cite journal | vauthors = Sperti S, Montanaro L, Mattioli A, Stirpe F | title = Inhibition by ricin of protein synthesis in vitro: 60 S ribosomal subunit as the target of the toxin | journal = The Biochemical Journal | volume = 136 | issue = 3 | pages = 813–815 | date = November 1973 | pmid = 4360718 | pmc = 1166019 | doi = 10.1042/bj1360813 }}</ref> The depurination event rapidly and completely inactivates the ribosome, resulting in toxicity from inhibited protein synthesis. A single RTA molecule in the [[cytosol]] is capable of depurinating approximately 1500 [[ribosomes]] per minute.

=== Depurination reaction ===
Within the active site of RTA, there exist several invariant amino acid residues involved in the [[depurination]] of ribosomal RNA.<ref name=pmid14579547/> Although the exact mechanism of the event is unknown, key amino acid residues identified include [[tyrosine]] at positions 80 and 123, [[glutamic acid]] at position 177, and [[arginine]] at position 180. In particular, Arg180 and Glu177 have been shown to be involved in the [[catalytic]] mechanism, and not substrate binding, with [[enzyme kinetics|enzyme kinetic]] studies involving RTA mutants. The model proposed by Mozingo and Robertus,<ref name=pmid7990130/> based on X-ray structures, is as follows:
# Sarcin-ricin loop substrate binds RTA active site with target adenine stacking against tyr80 and tyr123.
# Arg180 is positioned such that it can [[Protonation|protonate]] ''N''-3 of adenine and break the bond between ''N''-9 of the adenine ring and ''C''-1' of the [[ribose]].
# [[Bond cleavage]] results in an [[oxycarbonium]] ion on the ribose, stabilized by Glu177.
# ''N''-3 protonation of adenine by Arg180 allows [[deprotonation]] of a nearby water molecule.
# Resulting [[hydroxyl]] attacks ribose [[carbonium ion]].
# Depurination of adenine results in a neutral ribose on an intact phosphodiester RNA backbone.

==Toxicity==
[[File:Castor beans1.jpg|thumb|Castor beans]]
[[File:Castor oil seeds in the Royal Botanic Gardens, Kew Economic Botany Collection.jpg|thumb|Castor oil seeds in the Royal Botanic Gardens, Kew Economic Botany Collection]]

Ricin is very toxic if [[inhalation|inhaled]], [[Injection (medicine)|injected]], or [[ingestion|ingested]]. It can also be toxic if dust contacts the eyes or if it is absorbed through damaged skin. It acts as a toxin by inhibiting [[protein biosynthesis|protein synthesis]].<ref name="Ujváry_2010">{{cite book | vauthors = Ujváry I | year = 2010 | title = Hayes´ Handbook of Pesticide Toxicology | edition = Third | editor = Krieger R | publisher=Elsevier, Amsterdam | pages = 119–229 |isbn = 978-0-12-374367-1 }}</ref><ref name="cdc.gov">{{Cite web|title = CDC – The Emergency Response Safety and Health Database: Biotoxin: RICIN – NIOSH|url = https://www.cdc.gov/niosh/ershdb/emergencyresponsecard_29750002.html|website = cdc.gov|access-date = 31 December 2015}}</ref>  Ricin is resistant, but not impervious, to digestion by [[Protease|peptidases]]. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract, where it may cause mucosal injuries. With appropriate treatment, most patients will make a good recovery.<ref name="Schep">{{cite journal | vauthors = Schep LJ, Temple WA, Butt GA, Beasley MD | title = Ricin as a weapon of mass terror--separating fact from fiction | journal = Environment International | volume = 35 | issue = 8 | pages = 1267–1271 | date = November 2009 | pmid = 19767104 | doi = 10.1016/j.envint.2009.08.004 | url = https://doaj.org/article/8879c3e296c248a8a1d47a6779390d6c | access-date = 12 December 2019 | url-status = dead | bibcode = 2009EnInt..35.1267S | archive-url = https://web.archive.org/web/20201105154825/https://doaj.org/article/8879c3e296c248a8a1d47a6779390d6c | archive-date = 5 November 2020 }}</ref><ref name="pmid6862467">{{cite journal | vauthors = Kopferschmitt J, Flesch F, Lugnier A, Sauder P, Jaeger A, Mantz JM | title = Acute voluntary intoxication by ricin | journal = Human Toxicology | volume = 2 | issue = 2 | pages = 239–242 | date = April 1983 | pmid = 6862467 | doi = 10.1177/096032718300200211 | s2cid = 21965711 }}</ref>

=== Symptoms ===
Because the symptoms are caused by failure to make protein, they may take anywhere from hours to days to appear, depending on the route of exposure and the dose. When ingested, gastrointestinal symptoms can manifest within six hours; these symptoms do not always become apparent. Within two to five days of exposure to ricin, its effects on the [[central nervous system]], [[adrenal glands]], [[kidney]]s, and [[liver]] appear.<ref name="cdc.gov"/>

Ingestion of ricin causes pain, inflammation, and hemorrhage in the mucosal membranes of the gastrointestinal system. Gastrointestinal symptoms quickly progress to severe nausea, vomiting, diarrhea, and difficulty swallowing ([[dysphagia]]). Haemorrhage causes bloody feces ([[melena]]) and vomiting blood ([[hematemesis]]). The low blood volume ([[hypovolemia]]) caused by gastrointestinal fluid loss can lead to organ failure in the [[pancreas]], kidney, liver, and GI tract and progress to shock. Shock and organ failure are indicated by [[Orientation (mental)|disorientation]], stupor, weakness, drowsiness, excessive thirst ([[polydipsia]]), low urine production ([[oliguria]]), and bloody urine ([[hematuria]]).<ref name="cdc.gov"/>

Symptoms of ricin inhalation are different from those caused by ingestion. Early symptoms include a cough and fever.<ref name="cdc.gov"/>

When skin or inhalation exposure occur, ricin can cause an [[allergy|allergic reaction]] to develop. This is indicated by swelling ([[edema]]) of the eyes and lips; [[asthma]]; bronchial irritation; dry, sore throat; congestion; skin redness ([[erythema]]); skin blisters ([[Blister|vesication]]); [[wheezing]]; itchy, watery eyes; chest tightness; and skin irritation.<ref name="cdc.gov"/>

=== Treatment ===
An [[antidote]] has been developed by the UK military, although as of 2006 it has not yet been tested on humans.<ref>{{cite news| vauthors = Rincon P |url=http://news.bbc.co.uk/1/hi/sci/tech/8351666.stm |title=Ricin 'antidote' to be produced |publisher=[[BBC News]] |date=11 November 2009 |access-date=1 September 2010}}</ref><ref>{{cite web|url=http://www.utsouthwestern.edu/utsw/cda/dept37389/files/271161.html |title=Human trial proves ricin vaccine safe, induces neutralizing antibodies; further tests planned |publisher=[[University of Texas Southwestern Medical Center]] |date=30 January 2006 |access-date=7 May 2012 |url-status=dead |archive-url=https://web.archive.org/web/20110927092634/http://www.utsouthwestern.edu/utsw/cda/dept37389/files/271161.html |archive-date=27 September 2011 }}</ref> As of 2005 another antidote developed by the US military has been shown to be safe and effective in lab mice injected with [[antibody]]-rich blood mixed with ricin, and has had some human testing.<ref>{{cite web| vauthors = Fleming-Michael K |url= http://www.dcmilitary.com/dcmilitary_archives/stories/090105/36813-1.shtml |archive-url=https://archive.today/20120524162658/http://www.dcmilitary.com/dcmilitary_archives/stories/090105/36813-1.shtml |url-status=dead |archive-date=24 May 2012 |title=Vaccine for ricin toxin developed at Detrick lab |publisher=Dcmilitary.com |date=1 September 2005 |access-date=1 September 2010}}</ref> [[Monoclonal antibody|Monoclonal antibodies]] are under scientific investigation as a possible treatment for ricin poisoning.<ref>{{cite journal | vauthors = Orsini Delgado ML, Avril A, Prigent J, Dano J, Rouaix A, Worbs S, Dorner BG, Rougeaux C, Becher F, Fenaille F, Livet S, Volland H, Tournier JN, Simon S | title = Ricin Antibodies' Neutralizing Capacity against Different Ricin Isoforms and Cultivars | journal = Toxins | volume = 13 | issue = 2 | page = 100 | date = January 2021 | pmid = 33573016 | pmc = 7911099 | doi = 10.3390/toxins13020100 | doi-access = free }}</ref>

[[Symptom]]atic and supportive treatments are available for ricin poisoning. Existing treatments emphasize minimizing the effects of the poison. Possible treatments include [[intravenous fluids]] or electrolytes, [[airway management]], [[assisted ventilation]], or giving medications to remedy seizures and low blood pressure.  If the ricin has been ingested recently, the stomach can be flushed by ingesting [[activated charcoal]] or by performing [[gastric lavage]]. Survivors often develop long-term organ damage. Ricin causes severe [[diarrhea]] and vomiting, and victims can die of [[shock (circulatory)|circulatory shock]] or organ failure; inhaled ricin can cause fatal [[pulmonary edema]] or [[respiratory failure]]. Death typically occurs within 3–5 days after oral ingestion.<ref name="cdc.gov"/>

=== Prevention ===
Vaccination is possible by injecting an inactive form of protein chain A.<ref name="Harkup-2015" /> This vaccination is effective for several months due to the body's production of antibodies to the foreign protein. In 1978 Bulgarian defector Vladimir Kostov survived a ricin attack similar to the one on [[Georgi Markov]], probably due to his body's production of antibodies. When a ricin-laced pellet was removed from the small of his back it was found that some of the original wax coating was still attached. For this reason only small amounts of ricin had leaked out of the pellet, producing some symptoms but allowing his body to develop immunity to further poisoning.<ref name="Harkup-2015" />

=== Sources ===
The seeds of ''Ricinus communis'' are commonly crushed to extract [[castor oil]].  As ricin is not oil-soluble, little is found in the extracted castor oil.<ref name="Harkup-2015" /> The extracted oil is also heated to more than {{convert|80|C|F}} to [[Denaturation (biochemistry)|denature]] any ricin that may be present.<ref name="Harkup-2015" /> The remaining spent crushed seeds, called variously the "cake", "[[oil cake]]", and "press cake", can contain up to 5% ricin.<ref name="Levy-2011">{{Cite book|title = Poison: An Illustrated History| vauthors = Levy J |publisher = Lyons Press|year = 2011|isbn = 978-0-7627-7056-4|location = Guilford, Connecticut|page = 133}}</ref> While the oil cake from coconut, peanuts, and sometimes cotton seeds can be used as cattle feed or fertilizer, the toxic nature of castor beans precludes their oil cake from being used as feed unless the ricin is first deactivated by [[autoclave|autoclaving]].<ref name="urloil cake (chemistry) -- Encyclopædia Britannica">{{cite encyclopedia | url = http://www.britannica.com/EBchecked/topic/426145/oil-cake | title = Oil cake (chemistry) | encyclopedia = Encyclopædia Britannica}}</ref> Accidental ingestion of ''Ricinus communis'' cake intended for fertilizer has been reported to be responsible for fatal ricin poisoning in animals.<ref name="Ujváry_2010" /><ref name="pmid12046967">{{cite journal | vauthors = Soto-Blanco B, Sinhorini IL, Gorniak SL, Schumaher-Henrique B | title = Ricinus communis cake poisoning in a dog | journal = Veterinary and Human Toxicology | volume = 44 | issue = 3 | pages = 155–156 | date = June 2002 | pmid = 12046967 }}</ref>

Deaths from ingesting castor plant seeds are rare, partly because of their indigestible [[Seed#Seed coat|seed coat]], and because some of the ricin is deactivated in the stomach.<ref name=aplin>{{cite journal | vauthors = Aplin PJ, Eliseo T | title = Ingestion of castor oil plant seeds | journal = The Medical Journal of Australia | volume = 167 | issue = 5 | pages = 260–261 | date = September 1997 | pmid = 9315014 | doi = 10.5694/j.1326-5377.1997.tb125050.x | s2cid = 42009654 }}</ref> The pulp from eight beans is considered dangerous to an adult.<ref name="pmid3964368">{{cite journal | vauthors = Wedin GP, Neal JS, Everson GW, Krenzelok EP | title = Castor bean poisoning | journal = The American Journal of Emergency Medicine | volume = 4 | issue = 3 | pages = 259–261 | date = May 1986 | pmid = 3964368 | doi = 10.1016/0735-6757(86)90080-X }}</ref> Rauber and Heard have written that close examination of early 20th century [[case report]]s indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management".<ref name="pmid4082461">{{cite journal | vauthors = Rauber A, Heard J | title = Castor bean toxicity re-examined: a new perspective | journal = Veterinary and Human Toxicology | volume = 27 | issue = 6 | pages = 498–502 | date = December 1985 | pmid = 4082461 }}</ref>

Most acute poisoning episodes in humans are the result of oral ingestion of castor beans, 5–20 of which could prove fatal to an adult. Swallowing castor beans rarely proves to be fatal unless the bean is thoroughly chewed. The survival rate of castor bean ingestion is 98%.<ref name="Harkup-2015" /> In 2013 a 37-year-old woman in the United States survived after ingesting 30 beans.<ref>{{cite news |url=http://www.sltrib.com/sltrib/news/56953989-78/amp-woman-north-ricin.html.csp |title=Survived after ingesting 30 castor beans |access-date=3 August 2014 |newspaper=The Salt Lake Tribune | date=3 October 2013}}</ref> In another case, a man ingested 200 castor beans mixed with juice in a blender and survived.<ref>{{cite journal | vauthors = Benamor M, Gharbi E, Bouzid S, Chakroun-Walha O, Rekik N | title = Ricin poisoning after oral ingestion of castor beans: A case report and literature review | journal = African Journal of Emergency Medicine | volume = 10 | issue = 4 | pages = 274–276 | date = December 2020 | pmid = 33299763 | pmc = 7700980 | doi = 10.1016/j.afjem.2020.06.002 }}</ref>   Victims often manifest [[nausea]], [[diarrhea]], [[tachycardia|fast heart rate]], [[hypotension|low blood pressure]], and [[seizure]]s persisting for up to a week.<ref name="Ujváry_2010"/> Blood, plasma, or urine ricin or [[ricinine]] concentrations may be measured to confirm diagnosis. The laboratory testing usually involves immunoassay or [[Liquid chromatography–mass spectrometry|liquid chromatography-mass spectrometry]].<ref name="isbn0-9626523-7-7">{{cite book | vauthors = Baselt RC | title = Disposition of Toxic Drugs and Chemicals in Man | publisher = Biomedical Publications | location = Seal Beach, California | year = 2011 | pages = 1497–1499| isbn = 978-0-9626523-8-7 | edition = Ninth }}</ref>

== Therapeutic applications ==
{{More citations needed section|date=March 2014}}
Although no approved therapeutics are currently based on ricin, it does have the potential to be used in the [[chemotherapy|treatment of tumors]], as a "magic bullet" to destroy targeted cells.<ref name=pmid14579547/> Because ricin is a protein, it can be linked to a [[monoclonal antibody]]<ref>{{cite journal | vauthors = Raso V, Ritz J, Basala M, Schlossman SF | title = Monoclonal antibody-ricin A chain conjugate selectively cytotoxic for cells bearing the common acute lymphoblastic leukemia antigen | journal = Cancer Research | volume = 42 | issue = 2 | pages = 457–464 | date = February 1982 | pmid = 6948605 }}</ref> to target [[malignant|cancerous]] cells recognized by the antibody. The major problem with ricin is that its native [[Endocytosis|internalization]] sequences are distributed throughout the protein. If any of these native internalization sequences are present in a therapeutic agent, the drug will be internalized by, and kill, untargeted non-tumorous cells as well as targeted cancerous cells.

Modifying ricin may sufficiently lessen the likelihood that the ricin component of these [[immunotoxin]]s will cause the wrong cells to internalize it, while still retaining its cell-killing activity when it is internalized by the targeted cells. However, bacterial toxins, such as [[diphtheria toxin]], which is used in [[denileukin diftitox]], an FDA-approved treatment for leukemia and lymphoma, have proven to be more practical. A promising approach for ricin is to use the non-toxic B subunit (a lectin) as a vehicle for delivering [[antigen]]s into cells, thus greatly increasing their [[immunogenicity]]. Use of ricin as an [[adjuvant]] has potential implications for developing [[mucosal]] [[vaccine]]s.

== Regulation ==
In the US, ricin appears on the [[select agent]]s list of the [[US Department of Health and Human Services|Department of Health and Human Services]],<ref>{{cite web|url=https://www.cdc.gov/od/sap/docs/salist.pdf |title=HHS and USDA Select Agents and Toxins 7 CFR Part 331, 9 CFR Part 121, and 42 CFR Part 73 |website=cdc.gov |url-status=dead |archive-url=https://web.archive.org/web/20090117165906/http://www.cdc.gov/od/sap/docs/salist.pdf |archive-date=17 January 2009 }}</ref> and scientists must register with HHS to use ricin in their research. However, investigators under the control of less than 1000&nbsp;mg are exempt from regulation.<ref>{{cite web|title=Permissible Toxin Amounts |url=https://www.selectagents.gov/PermissibleToxinAmounts.html |publisher=National Select Agent Registry |date=September 10, 2020}}</ref>

Ricin is classified as an [[List of extremely hazardous substances|extremely hazardous substance]] in the United States as defined in Section 302 of the US [[Emergency Planning and Community Right-to-Know Act]] (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.<ref name="gov-right-know">{{Cite journal | publisher = [[United States Government Publishing Office|Government Printing Office]] | title = 40 C.F.R.: Appendix A to Part 355 – The List of Extremely Hazardous Substances and Their Threshold Planning Quantities | url = http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf |journal=Code of Federal Regulations| edition = 1 July 2008 | access-date = 29 October 2011 | archive-url = https://web.archive.org/web/20120225051612/http://edocket.access.gpo.gov/cfr_2008/julqtr/pdf/40cfr355AppA.pdf | archive-date = 25 February 2012 | url-status = dead }}</ref>

== Chemical or biological warfare agent ==
===History===
[[File:October 2003 ricin letter metal vial.jpg|thumb|A metal vial containing ricin from the [[2003 ricin letters]]]]
The United States investigated ricin for its military potential during [[World War I]].<ref name="Augerson2000">{{cite report | vauthors = Augerson WS, Spektor DM | publisher = United States Dept. of Defense, Office of the Secretary of Defense, National Defense Research Institute (U.S.) | date = 2000 | title = A Review of the Scientific Literature as it Pertains to Gulf War Illnesses. | volume = 5 |series=Chemical and Biological Warfare Agents | work = Rand Corporation | doi = 10.7249/MR1018.5 | isbn = 978-0-8330-2680-4}}{{page needed|date=April 2013}}</ref> At that time it was being considered for use either as a toxic dust or as a coating for bullets and [[Shrapnel shell|shrapnel]]. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the [[Hague Conventions (1899 and 1907)|Hague Convention of 1899]] (adopted in U.S. law at 32 [[United States Statutes at Large|Stat.]] 1903), specifically Annex §2, Ch.1, Article 23, stating "...&nbsp;it is especially prohibited&nbsp;... [t]o employ poison or poisoned arms".<ref>{{cite web|url=http://avalon.law.yale.edu/19th_century/hague02.asp#art23 |title=The Avalon Project&nbsp;– Laws of War: Laws and Customs of War on Land (Hague II); July 29, 1899 |publisher=Avalon.law.yale.edu |access-date=1 September 2010}}</ref>

During [[World War II]] the United States and Canada studied ricin in [[cluster bomb]]s.<ref name="Gupta_2009">{{cite book | vauthors = Gupta R | title = Handbook of Toxicology of Chemical Warfare Agents | publisher = Academic Press | location = Boston | year = 2009 | isbn = 978-0-12-374484-5 }}{{page needed|date=April 2013}}</ref> Though there were plans for mass production and several field trials with different bomblet concepts, the end conclusion was that it was no more economical than using [[phosgene]]. This conclusion was based on comparison of the final weapons, rather than ricin's toxicity ([[LD50|LCt<sub>50</sub>]] ~10&nbsp;mg/min·m<sup>3</sup>).{{Citation needed|date=January 2024}} Ricin was given the [[chemical weapon designation|military symbol]] '''W''' or later '''WA'''.{{Citation needed|date=January 2024}}  Interest in it continued for a short period after World War II, but soon subsided when the [[Chemical Corps|US Army Chemical Corps]] began a program to weaponize [[sarin]].<ref name="Romano_2007">{{cite book | vauthors = Romano Jr JA, Salem M, Lukey BJ | title = Chemical Warfare Agents: Chemistry, Pharmacology, Toxicology, and Therapeutics, Second Edition | publisher = CRC Press | year = 2007 | pages = 437 | isbn = 978-1-4200-4662-5 }}</ref>

The [[Soviet Union]] possessed weaponized ricin. The [[KGB]] developed weapons using ricin which were used outside the [[Soviet Bloc|Soviet bloc]], most famously in the [[Georgi Markov|Markov assassination]].<ref>{{cite book |last1=Cummings |first1=Richard H. |title=Cold War Radio: The Dangerous History of American Broadcasting in Europe, 1950-1989 |date=22 April 2009 |publisher=McFarland |isbn=978-0-7864-5300-9 |pages=67–70 |url=https://books.google.com/books?id=Kfl-8vMB0jEC |language=en}}</ref><ref>{{cite news| last=Edwards | first=Richard | title=Poison-tip umbrella assassination of Georgi Markov reinvestigated | newspaper=The Telegraph | date=19 June 2008 | url=https://www.telegraph.co.uk/news/2158765/Poison-tip-umbrella-assassination-of-Georgi-Markov-reinvestigated.html|archive-url=https://ghostarchive.org/archive/20220112/https://www.telegraph.co.uk/news/2158765/Poison-tip-umbrella-assassination-of-Georgi-Markov-reinvestigated.html |archive-date=12 January 2022|url-status=live }}</ref>

===Control===
In spite of ricin's extreme [[toxicity]] and utility as an agent of chemical/biological warfare, production of the toxin is difficult to limit. The [[castor bean]] plant from which ricin is derived is a common [[ornamental plant|ornamental]] and can be grown at home without any special care.

Under both the 1972 [[Biological Weapons Convention]] and the 1997 [[Chemical Weapons Convention]], ricin is listed as a [[List of Schedule 1 substances (CWC)|schedule 1 controlled substance]]. Despite this, more than {{convert|1|e6MT|ST|abbr=off}} of castor beans are processed each year, and approximately 5% of the total is rendered into a waste containing negligible concentrations of undenatured ricin toxin.<ref name="http://www.ansci.cornell.edu/plants/toxicagents/ricin.html">{{cite web|url=http://www.ansci.cornell.edu/plants/toxicagents/ricin.html |title=Cornell University Department of Animal Science |publisher=Ansci.cornell.edu |access-date=7 May 2012}}</ref>

Ricin is several orders of magnitude less toxic than [[botulinum]] or [[tetanus toxin]], but the latter are harder to come by. Compared to botulinum or [[anthrax]] as [[biological weapon]]s or [[chemical weapon]]s, the quantity of ricin required to achieve LD<sub>50</sub> over a large geographic area is significantly more than an agent such as anthrax (tons of ricin vs. only kilogram quantities of anthrax).<ref name="pmid10458957">{{cite journal | vauthors = Kortepeter MG, Parker GW | title = Potential biological weapons threats | journal = Emerging Infectious Diseases | volume = 5 | issue = 4 | pages = 523–527 | year = 1999 | pmid = 10458957 | pmc = 2627749 | doi = 10.3201/eid0504.990411 }}</ref> Ricin is easy to produce, but is not as practical or likely to cause as many casualties as other agents.<ref name="Schep"/> Ricin is easily denatured by temperatures over {{convert|80|C|F}} meaning many methods of deploying ricin would generate enough heat to denature it.<ref name="Levy-2011" /> Once deployed, an area contaminated with ricin remains dangerous until the bonds between chain A or B have been broken, a process that takes two or three days.<ref name="Harkup-2015" /> In contrast, anthrax [[endospore|spore]]s may remain lethal for decades. [[Jan van Aken (Politician)|Jan van Aken]], a German expert on biological weapons, explained in a report for [[The Sunshine Project]] that [[Al Qaeda]]'s experiments with ricin suggest their inability to produce [[botulinum toxin|botulinum]] or anthrax.<ref name="vanaken2001">{{cite web | vauthors = van Aken J | year = 2001 | archive-url = https://archive.today/20130108235747/http://www.sunshine-project.org/publications/bk/bk7en.html | archive-date = 8 January 2013 | url = http://www.sunshine-project.org/publications/bk/bk7en.html | title = Biological Weapons: Research Projects of the German Army | work = Backgrounder Series No. 7 | publisher = [[The Sunshine Project]] | url-status = dead }}</ref>

== Vaccination ==

[[File:RTAvaccines.jpg|thumb|400px| Ricin toxin, RiVax, RTA1-33/44-198, and a single domain antibody-antigen complex with the RTA1-33/44-198 immunogen. Original figure can be found in Legler, et al.<ref name="pmid27660893">{{cite journal | vauthors = Legler PM, Compton JR, Hale ML, Anderson GP, Olson MA, Millard CB, Goldman ER | title = Stability of isolated antibody-antigen complexes as a predictive tool for selecting toxin neutralizing antibodies | journal = mAbs | volume = 9 | issue = 1 | pages = 43–57 | date = January 2017 | pmid = 27660893 | pmc = 5240650 | doi = 10.1080/19420862.2016.1236882 }}</ref><ref name="Legler_2011">{{cite journal | vauthors = Legler PM, Brey RN, Smallshaw JE, Vitetta ES, Millard CB | title = Structure of RiVax: a recombinant ricin vaccine | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 67 | issue = Pt 9 | pages = 826–830 | date = September 2011 | pmid = 21904036 | pmc = 3169317 | doi = 10.1107/S0907444911026771 | bibcode = 2011AcCrD..67..826L }}</ref>]] 

Ricin toxin vaccines have emerged as a focus in [[biodefense]] research. Two recombinant A subunit (RTA)-based vaccines, RiVax and RVEc (also known as RTA1-33/44-198),<ref name="pmid15187223">{{cite journal | vauthors = Olson MA, Carra JH, Roxas-Duncan V, Wannemacher RW, Smith LA, Millard CB | title = Finding a new vaccine in the ricin protein fold | journal = Protein Engineering, Design & Selection | volume = 17 | issue = 4 | pages = 391–397 | date = April 2004 | pmid = 15187223 | doi = 10.1093/protein/gzh043 }}</ref><ref name="pmid23364220">{{cite journal | vauthors = Janosi L, Compton JR, Legler PM, Steele KE, Davis JM, Matyas GR, Millard CB | title = Disruption of the putative vascular leak peptide sequence in the stabilized ricin vaccine candidate RTA1-33/44-198 | journal = Toxins | volume = 5 | issue = 2 | pages = 224–248 | date = January 2013 | pmid = 23364220 | pmc = 3640533 | doi = 10.3390/toxins5020224 | doi-access = free }}</ref> have completed Phase I clinical trials, and were found to be safe.<ref name="Vance_2016">{{cite journal | vauthors = Vance DJ, Mantis NJ | title = Progress and challenges associated with the development of ricin toxin subunit vaccines | journal = Expert Review of Vaccines | volume = 15 | issue = 9 | pages = 1213–1222 | date = September 2016 | pmid = 26998662 | pmc = 5193006 | doi = 10.1586/14760584.2016.1168701 }}</ref> These vaccines are based on modified versions of the ricin toxin A-chain, designed to reduce toxicity while maintaining [[immunogenicity]].

==Developments==
A biopharmaceutical company called Soligenix, Inc. licensed an anti-ricin vaccine called RiVax<ref>{{cite journal | vauthors = Legler PM, Brey RN, Smallshaw JE, Vitetta ES, Millard CB | title = Structure of RiVax: a recombinant ricin vaccine | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 67 | issue = Pt 9 | pages = 826–830 | date = September 2011 | pmid = 21904036 | pmc = 3169317 | doi = 10.1107/S0907444911026771 | bibcode = 2011AcCrD..67..826L }}</ref> from Vitetta et al. at [[University of Texas Southwestern Medical Center|UT Southwestern]]. The vaccine was found safe and immunogenic in mice, rabbits, and humans. Two successful clinical trials were completed.<ref>{{cite web|title=RiVax™ Ricin Toxin Vaccine |url=http://www.soligenix.com/pipeline/vaccinesbiodefense/rivax-ricin-toxin-vaccine/|publisher=Soligenix, Inc|access-date=28 June 2017 }}</ref> Soligenix was issued a US patent for Rivax. The ricin vaccine candidate was granted orphan drug status in the US and the EEC and, as of 2019, was in clinical trials in the US. Grants from the National Institute of Allergy and Infectious Diseases and the US Food and Drug Administration supported development of the vaccine candidate.<ref>{{cite web | vauthors = Hackett DW |title=Ricin Vaccine Candidate Rivax Awarded Patent Protection |url=https://www.precisionvaccinations.com/soligenix-rivax-ricin-vaccine-candidate-receives-patent-expanding-protection |website=Precision Vaccinations |publisher=Precision Vax Llc |access-date=27 February 2019 |location=Houston TX |date=11 February 2019}}</ref>

== Synthesis ==
The first isolation of ricin is attributed to the Baltic-German microbiologist [[Peter Hermann Stillmark]] (1860–1923) in 1888.<ref>{{cite thesis |last = Stillmark |first = Hermann | date = 1888 | title = Über Ricin, ein giftiges Ferment aus den Samen von Ricinus comm. L. und einigen anderen Euphorbiaceen | trans-title = About ricin, a poisonous ferment [i.e., enzyme] from the seeds of ''Ricinus communis'' L. and some other ''Euphorbiaceae'' | language = German | degree = M.D. | publisher = University of Dorpat | location = Dorpat, Estonia }}</ref><ref>{{cite journal | vauthors = Stillmark H | title=Ueber ricin |journal=Arbeiten des Pharmakologischen Institutes zu Dorpat |date=1889 |volume=3 |pages=59–151 |url=https://books.google.com/books?id=O_7qAAAAMAAJ&pg=PA59 |trans-title=About ricin |language=German}}</ref><ref>The Russian physician N.A. Bubnow and the Australian physician Thomas Storie Dixson (1854–1932) probably isolated ricin in 1887 at the University of Strassburg (Strasbourg), Germany; however, Dixson mistakenly believed that ricin was a [[glycoside]], whereas it is actually a protein.
*  {{cite journal |last1=Dixson |first1=Thomas |title=Ricinus communis |journal=Australasian Medical Gazette |date=March 1887 |volume=6 |pages=137–138, 155–158 |url=https://babel.hathitrust.org/cgi/pt?id=hvd.32044103020863&view=1up&seq=147}}
*  {{cite book |vauthors = Vogl A |title=Pharmakognosie |date=1892 |publisher=Carl Gerold's Sohn |location=Vienna, Austria |page=204 |url=https://www.biodiversitylibrary.org/item/23165#page/208/mode/1up |language=German}} From p. 204: ''"Bubnow und Dixson (1887) erhielten aus den entfetteten Samen … vielleicht eine sogenannte Phytalalbumose darstellt."'' (Bubnow and Dixson (1887) obtained, from the defatted seeds by extraction with dilute hydrochloric acid, a glycoside ([which they called] Ricinon) that belongs to the acid anhydrides [and that is] of very drastic effect.  Mr. Stillmark (1889) finally precipitated, from the seeds and oilcake, a very poisonous substance, Ricin, (about 3% of the air-dried seeds) that's insoluble in alcohol and that probably is a protein, an amorphous enzyme, perhaps a so-called phytalbumin.)
*  {{cite journal | vauthors = Finnemore H |title=Castor oil – part 1 |journal=Pharmaceutical Journal |date=29 July 1905 |volume=75 |pages=137–138 |url=https://books.google.com/books?id=E4BMAQAAMAAJ&pg=PA137}} See p. 137. 
*  {{cite Australian Dictionary of Biography | vauthors = Cook B |id2=dixson-thomas-storie-6342 | title = Dixson, Thomas Storie (1854–1932) }}</ref>

==Terrorist use==
{{main|List of incidents involving ricin}}
Ricin has been involved in a number of actual or planned attacks on individuals. In 1978, the Bulgarian dissident [[Georgi Markov]] was assassinated by [[Bulgarian secret police]] who surreptitiously shot him on a London street with what was later found to have been a [[Bulgarian umbrella|modified umbrella]] using [[compressed gas]] to fire a tiny pellet containing ricin into his leg.<ref name="Schep"/><ref>{{cite news |url=http://www.cnn.com/2003/WORLD/europe/01/07/terror.poison.bulgarian/ |title=Ricin and the umbrella murder |access-date=15 March 2008 |publisher=[[CNN]] |date=7 January 2003}}</ref> He died in a hospital a few days later; his body was passed to a special poison branch of the [[British Ministry of Defence]] that discovered the pellet during an [[autopsy]]. The prime suspects were the Bulgarian secret police: Georgi Markov had [[defection|defected]] from Bulgaria some years previously and had subsequently written books and made radio broadcasts that were highly critical of the Bulgarian [[communist regime]]. However, it was believed at the time that Bulgaria would not have been able to produce the pellet, and it was also believed that the KGB had supplied it. The KGB denied any involvement, although high-profile KGB defectors [[Oleg Kalugin]] and [[Oleg Gordievsky]] later confirmed the KGB's involvement. Soviet dissident [[Aleksandr Solzhenitsyn]] developed (but survived) ricin-like symptoms after an encounter in 1971 with KGB agents.<ref>{{cite book | vauthors = Thomas DM |title=Alexander Solzhenitsyn: A Century in His Life |pages=368–378 |publisher=St. Martin's Press |isbn=978-0-7567-6011-3 |year=1998 |edition=First}}</ref>

Ten days before the attack on Georgi Markov another Bulgarian defector, [[Vladimir Kostov]], survived a similar attack. Kostov was standing on an escalator of the Paris metro when he felt a sting in his lower back above the belt of his trousers. He developed a fever, but recovered. After Markov's death the wound on Kostov's back was examined and a ricin-laced pellet identical to the one used against Markov was removed.<ref name="Harkup-2015" />

Several terrorist individuals and groups have experimented with ricin or planned to use it.<ref>{{cite news| title=Internet dating couple jailed for plotting IS attack in Britain | newspaper=Guernsey Press | date=22 February 2018 | url=https://guernseypress.com//news/uk-news/2018/02/22/internet-dating-couple-jailed-for-plotting-is-attack-in-britain/}} One of many news items on plots to use ricin for terrorism.</ref> There have been incidents of the poison being mailed to US politicians. For example, on 29 May 2013 two anonymous letters sent to New York City Mayor [[Michael Bloomberg]] contained traces of it.<ref name="urlLetters to NYC Mayor Bloomberg contained ricin">{{cite web |url=http://news.msn.com/us/letter-to-nyc-mayor-bloomberg-contained-ricin |archive-url=https://archive.today/20130616004814/http://news.msn.com/us/letter-to-nyc-mayor-bloomberg-contained-ricin |url-status=dead |archive-date=16 June 2013 |title=Letters to NYC Mayor Bloomberg contained ricin |agency=Associated Press |date=30 May 2013 |publisher=MSN News }}</ref> Another was sent to the offices of [[Mayors Against Illegal Guns]] in Washington, D.C. A letter containing ricin was also reported to have been sent to American President [[Barack Obama]] at the same time. [[Shannon Richardson]], an actress, was later charged with the crime, and pleaded guilty that December;<ref>{{cite news |url=https://www.theguardian.com/world/2013/jun/08/shannon-richardson-ricin-plot-husband |title=Bit-part actor charged over plot to frame husband for ricin letters | vauthors = Harris P |work=[[The Guardian]] |date=8 June 2013}}</ref> she was sentenced to 18 years in prison plus a [[restitution]] fine of [[US$]]367,000.<ref>{{cite news|url=https://edition.cnn.com/2014/07/16/justice/texas-ricin-actress-sentenced/index.html?hpt=hp_t3|title=Texas actress who sent Obama ricin sentenced to 18 years | vauthors = McLaughlin EC |publisher=CNN|date=16 July 2014|access-date=16 July 2014}}</ref> On 2 October 2018, two letters suspected of containing ricin were sent to [[The Pentagon]], one addressed to Secretary of Defense [[James Mattis]], and the other to Chief of Naval Operations, Admiral [[John M. Richardson (admiral)|John Richardson]].<ref name="urlRicin detected in mail sent to Pentagon">{{cite web |url=http://www.cnn.com/2018/10/02/politics/pentagon-ricin-mail/index.html |title=Ricin detected in mail sent to Pentagon |date=10 October 2018 |publisher=CNN}}</ref> A letter was received on 23 July 2019 at [[Pelican Bay State Prison]] in California which claimed to contain a suspicious substance. Authorities later confirmed it contained ricin; no detrimental exposures were identified.<ref name="pelican bay">{{cite news | title=Suspicious substance which caused Pelican Bay building evacuation identified as ricin | vauthors = Maravelias P | date=27 July 2019 | url=https://krcrtv.com/north-coast-news/eureka-local-news/suspicious-substance-which-caused-pelican-bay-building-evacuation-identified-as-ricin | website=[[KRCR-TV]]}}</ref>

In 2020, some media in the Czech Republic reported, based on intelligence information, that a person carrying a Russian diplomatic passport and ricin had arrived in Prague with the intention of assassinating three politicians. Russian president [[Vladimir Putin]] denied the reports. The targets were said to have been [[Zdeněk Hřib]], the mayor of [[Prague]] (capital of the Czech Republic), who was involved in renaming a square in Prague, "Pod Kaštany", where the Russian embassy is situated, to the Square of [[Boris Nemtsov]], an opposition politician assassinated in the  [[Kremlin]] in 2015; [[Ondřej Kolář (politician)|Ondřej Kolář]], the mayor of [[Prague 6]] municipal district, who was involved in removing the controversial statue to the Soviet-era [[Marshal Konev]]; and [[Pavel Novotný (politician)|Pavel Novotný]], the mayor of Prague's southwestern [[Řeporyje]] district. They all received police protection.<ref name="prague-guardian">{{cite news | vauthors = Roth A |title=Prague mayor under police protection amid reports of Russian plot |url=https://www.theguardian.com/world/2020/apr/27/prague-mayor-under-police-protection-amid-reports-russian-plot-zdenek-hrib |access-date=29 April 2020 |work=The Guardian |date=27 April 2020}}</ref><ref name="prague_bbc">{{cite news |title=Police protecting Prague mayor after 'murder plot' |url=https://www.bbc.com/news/world-europe-52455223 |access-date=29 April 2020 |work=BBC News |date=29 April 2020}}</ref> Czech president [[Miloš Zeman]] later described the police protection of Zdeněk Hřib as an attempt by an insignificant politician to gain attention. Zeman also confused ricin with non-poisonous [[laxative]] [[castor oil]].<ref>{{Cite web|title=Czech president lashes out at Prague mayor under police protection|url=https://www.politico.eu/article/milos-zeman-czech-president-lashes-out-at-prague-mayor-under-police-protection/| vauthors = Mortkowitz S |date=6 May 2020|website=Politico|access-date=7 May 2020}}</ref>

In 2018<ref>{{cite news|agency=Associated Press | title=German prosecutors arrest man over alleged ricin attack plot |newspaper=The Guardian | date=14 June 2018 | url=http://www.theguardian.com/world/2018/jun/14/german-prosecutors-arrest-man-over-plot-to-launch-ricin-attack}}</ref> and 2023 German police thwarted attempted ricin attacks, after tip-offs believed to have come from the US [[FBI]].<ref>{{cite news| last=Connolly | first=Kate | title=German police arrest Iranian man suspected of planning chemical attack |newspaper=The Guardian | date=8 January 2023 | url=https://www.theguardian.com/world/2023/jan/08/german-police-arrest-iranian-man-suspected-of-planning-chemical-attack}}</ref>

==In popular culture==
Ricin has been used as a plot device, such as in the television series ''[[Breaking Bad]]''.<ref name="breaking">{{cite web |date=27 September 2013 |title=Things You Should Know About Ricin Before Watching the 'Breaking Bad' Finale |url=http://voices.nationalgeographic.com/2013/09/27/things-you-should-know-about-ricin-before-watching-the-breaking-bad-finale/ |url-status=dead |archive-url=https://web.archive.org/web/20210308165945/http://blog.nationalgeographic.org/2013/09/27/things-you-should-know-about-ricin-before-watching-the-breaking-bad-finale/ |archive-date=8 March 2021 |access-date=2 May 2015 |website=[[National Geographic (magazine)|National Geographic]] |publisher=[[National Geographic Society]]}}</ref>

The popularity of ''Breaking Bad'' inspired several real-life criminal cases involving ricin or similar substances. Kuntal Patel from London attempted to poison her mother with [[abrin]] after the latter interfered with her marriage plans.<ref name="patel">{{cite news |url=https://www.theguardian.com/uk-news/2014/sep/22/woman-poison-plot-mother-breaking-bad-court |title=Woman tried to poison mother in plot inspired by Breaking Bad, court told |date=22 September 2014 |website=[[The Guardian]] |location=London |access-date=2 May 2015}}</ref> Daniel Milzman, a 19-year-old former [[Georgetown University]] student, was charged with manufacturing ricin in his dorm room, as well as the intent of "[using] the ricin on another undergraduate student with whom he had a relationship".<ref name="dorm">{{cite web |url=http://www.washingtontimes.com/news/2014/sep/15/guilty-plea-georgetown-university-ricin-case-ties-/ |title=Guilty plea in Georgetown University ricin case with tie to 'Breaking Bad' | vauthors = Noble A |date=15 September 2014 |website=[[The Washington Times]] |access-date=2 May 2015}}</ref> Mohammed Ali from [[Liverpool]], England, was convicted after attempting to purchase 500&nbsp;mg of ricin over the [[dark web]] from an undercover [[FBI agent]]. He was sentenced on 18 September 2015 to eight years imprisonment.<ref>{{Cite news|title = Breaking Bad fan guilty of Dark Web ricin plot|url = https://www.bbc.co.uk/news/uk-england-33708611|publisher = BBC News|access-date = 29 July 2015|date = 29 July 2015}}</ref>

In [[Agatha Christie]]'s novel ''[[Partners in Crime (short story collection)|Partners in Crime]]'','' The House of Lurking Death '',ricin was used as a plot device.<ref>{{Cite web |title=Andrew Wilson: Would Agatha Christie have solved the Salisbury poisoning? |website=Aitken Alexander Associates |url=https://aitkenalexander.co.uk/andrew-wilson-would-agatha-christie-have-solved-the-salisbury-poisoning |access-date=2025-01-26}}</ref>

== See also ==
* [[List of poisonous plants]]

== References ==
{{Reflist}}

== External links ==
{{Commons category}}
* [http://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox012.pdf Studies showing lack of toxicity of castor oil] from the [[Public Health Service|US Public Health Service]]
* [http://www.hort.purdue.edu/newcrop/afcm/castor.html Castor bean information] at [[Purdue University]]
* [http://www.ansci.cornell.edu/plants/toxicagents/ricin.html Plants Poisonous to Livestock] – Ricin information at [[Cornell University]]
* [http://news.bbc.co.uk/2/hi/health/2837763.stm Ricin cancer therapy tested] at [[BBC]]
* [https://web.archive.org/web/20050205181325/http://www.bt.cdc.gov/agent/ricin/ Ricin – Emergency Preparations] at [[Centers for Disease Control and Prevention|CDC]]
* [https://web.archive.org/web/20130602143109/http://www.bt.cdc.gov/agent/ricin/erc9009-86-3pr.asp Emergency Response Card – Ricin] at [[Centers for Disease Control and Prevention|CDC]]
* {{PDBe-KB2|P02879|Ricin}}

{{Chemical agents}}
{{Toxins}}
{{Lectins}}
{{Albumins}}
{{Authority control}}

[[Category:Ricin| ]]
[[Category:Biological toxin weapons]]
[[Category:Castor oil plant]]
[[Category:Lectins]]
[[Category:Legume lectins]]
[[Category:Plant toxins]]
[[Category:Proteins]]
[[Category:Ribosome-inactivating proteins]]
[[Category:Toxins]]