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Ricin ( ) is a lectin (a carbohydrate-binding
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
) and a highly potent
toxin A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849 ...
produced in the seeds of the castor oil plant, ''Ricinus communis''. The median lethal dose (LD50) of ricin for mice is around 22
micrograms In the metric system, a microgram or microgramme is a unit of mass equal to one millionth () of a gram. The unit symbol is μg according to the International System of Units (SI); the recommended symbol in the United States and United Kingdom ...
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 1 milligram per kilogram of body weight. Ricin was first described by Peter Hermann Stillmark, the founder of lectinology.


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 The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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 reductively cleaved.


Biosynthesis

Ricin is synthesized in the
endosperm The endosperm is a tissue produced inside the seeds of most of the flowering plants following double fertilization. It is triploid (meaning three chromosome sets per nucleus) in most species, which may be auxin-driven. It surrounds the embryo an ...
of castor oil plant seeds. The ricin precursor protein is 576
amino acid residue Protein structure is the three-dimensional arrangement of atoms in an amino acid-chain molecule. Proteins are polymers specifically polypeptides formed from sequences of amino acids, the monomers of the polymer. A single amino acid monomer ma ...
s in length and contains a
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-te ...
(residues 1–35), the ricin A chain (36–302), a linker peptide (303–314), and the ricin B chain (315–576). The
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
signal sequence delivers the prepropolypeptide to the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
(ER) and then the signal peptide is cleaved off. Within the lumen of the ER the propolypeptide is
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
and a protein disulfide isomerase catalyzes disulfide bond formation between cysteines 294 and 318. The propolypeptide is further glycosylated within the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
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.


Structure

In terms of structure, ricin closely resembles abrin-a, an isotoxin of abrin. The quaternary structure of ricin is a globular, glycosylated heterodimer of approximately 60–65 kDa. Ricin toxin A chain and ricin toxin B chain are of similar molecular weights, approximately 32 kDa and 34 kDa, respectively. * Ricin toxin A chain (RTA) is an N-
glycoside hydrolase Glycoside hydrolases (also called glycosidases or glycosyl hydrolases) catalyze the hydrolysis of glycosidic bonds in complex sugars. They are extremely common enzymes with roles in nature including degradation of biomass such as cellulose (cel ...
composed of 267 amino acids. It has three structural domains with approximately 50% of the polypeptide arranged into alpha-helices and beta-sheets. 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. RTB forms a bilobal, barbell-like structure lacking alpha-helices or beta-sheets where individual lobes contain three
subdomains In the Domain Name System (DNS) hierarchy, a subdomain is a domain that is a part of another (main) domain. For example, if a domain offered an online store as part of their website example.com, it might use the subdomain shop.example.com . Ov ...
. 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 Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley p ...
, are not toxic because without the link to protein chain B, protein chain A cannot enter the cell and do damage to ribosomes.


Entry into the cytoplasm

Ricin B chain binds complex carbohydrates on the surface of
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
cells containing either terminal N-acetylgalactosamine or beta-1,4-linked galactose residues. In addition, the
mannose Mannose is a sugar monomer of the aldohexose series of carbohydrates. It is a C-2 epimer of glucose. Mannose is important in human metabolism, especially in the glycosylation of certain proteins. Several congenital disorders of glycosylat ...
-type glycans of ricin are able to bind to cells that express mannose receptors. RTB has been shown to bind to the cell surface on the order of 106–108 ricin molecules per cell surface. The profuse binding of ricin to surface membranes allows internalization with all types of membrane invaginations. The holotoxin can be taken up by clathrin-coated pits, as well as by clathrin-independent pathways including caveolae and
macropinocytosis In cellular biology, pinocytosis, otherwise known as fluid endocytosis and bulk-phase pinocytosis, is a mode of endocytosis in which small molecules dissolved in extracellular fluid are brought into the cell through an invagination of the cell me ...
. Intracellular
vesicles Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features o ...
shuttle ricin to endosomes that are delivered to the
Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
. 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 A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
s offers little or no protection against ricin. Ricin molecules are thought to follow retrograde transport via early endosomes, the trans-Golgi network, and the Golgi to enter the lumen of the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
(ER). For ricin to function cytotoxically, RTA must be reductively cleaved from RTB to release a
steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
block of the RTA active site. This process is catalysed by the protein PDI (
protein disulphide isomerase Protein disulfide isomerase (), or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as th ...
) that resides in the lumen of the ER. 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. Roles for the ER chaperones GRP94, EDEM and BiP 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 Endoplasmic-reticulum-associated protein degradation (ERAD) designates a cellular pathway which targets misfolded proteins of the endoplasmic reticulum for ubiquitination and subsequent degradation by a protein-degrading complex, called the prote ...
) 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, 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. 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, which de-purinates ribosomes, thus halting protein synthesis.


Ribosome inactivation

RTA has rRNA N-glycosylase activity that is responsible for the cleavage of a glycosidic bond within the large
rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribos ...
of the
60S Ribosomal particles are denoted according to their sedimentation coefficients in Svedberg units. The 60S subunit is the large subunit of eukaryotic 80S ribosomes. It is structurally and functionally related to the 50S subunit of 70S prokaryotic ...
subunit of eukaryotic ribosomes. RTA specifically and irreversibly hydrolyses the N-glycosidic bond of the
adenine Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its deriv ...
residue at position 4324 (A4324) within the
28S 28S ribosomal RNA is the structural ribosomal RNA (rRNA) for the large subunit (LSU) of eukaryotic cytoplasmic ribosomes, and thus one of the basic components of all eukaryotic cells. It has a size of 25S in plants and 28S in mammals, hence th ...
rRNA, but leaves the phosphodiester backbone of the RNA intact. The ricin targets A4324 that is contained in a highly conserved sequence of 12
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
s universally found in eukaryotic ribosomes. The sequence, 5'-AGUACGAGAGGA-3', termed the sarcin-ricin loop, is important in binding elongation factors during protein synthesis. 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. Although the exact mechanism of the event is unknown, key amino acid residues identified include
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the G ...
at positions 80 and 123, glutamic acid at position 177, and
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
at position 180. In particular, Arg180 and Glu177 have been shown to be involved in the catalytic mechanism, and not substrate binding, with enzyme kinetic studies involving RTA mutants. The model proposed by Mozingo and Robertus, 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
protonate In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry aci ...
N-3 of adenine and break the bond between N-9 of the adenine ring and C-1' of the
ribose Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this com ...
. #
Bond cleavage In chemistry, bond cleavage, or bond fission, is the splitting of chemical bonds. This can be generally referred to as dissociation when a molecule is cleaved into two or more fragments. In general, there are two classifications for bond cleava ...
results in an oxycarbonium ion on the ribose, stabilized by Glu177. # N-3 protonation of adenine by Arg180 allows
deprotonation Deprotonation (or dehydronation) is the removal (transfer) of a proton (or hydron, or hydrogen cation), (H+) from a Brønsted–Lowry acid in an acid–base reaction.Henry Jakubowski, Biochemistry Online Chapter 2A3, https://employees.csbsju. ...
of a nearby water molecule. # Resulting
hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
attacks ribose
carbonium ion In chemistry, a carbonium ion is any cation that has a pentavalent carbon atom. The name carbonium may also be used for the simplest member of the class, properly called methanium (), where the five valences are filled with hydrogen atoms. The ...
. # Depurination of adenine results in a neutral ribose on an intact phosphodiester RNA backbone.


Toxicity

Ricin is very toxic if inhaled, injected, or 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 synthesis. It prevents cells from assembling various
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s into proteins according to the messages it receives from messenger RNA in a process conducted by the cell's ribosome (the protein-making machinery) – that is, the most basic level of cell metabolism, essential to all living cells and thus to life itself. Ricin is resistant, but not impervious, to digestion by
peptidases A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the form ...
. 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.


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 The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
,
adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
,
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s, and
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
appear. 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 Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or liq ...
). Haemorrhage causes bloody feces (
melena Melena or melaena refers to the dark black, tarry feces that are associated with upper gastrointestinal bleeding. The black color and characteristic strong odor are caused by hemoglobin in the blood being altered by digestive enzymes and intest ...
) and vomiting blood ( hematemesis). The low blood volume ( hypovolemia) caused by gastrointestinal fluid loss can lead to organ failure in the
pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...
, kidney, liver, and GI tract and progress to shock. Shock and organ failure are indicated by disorientation, stupor, weakness, drowsiness, excessive thirst (
polydipsia Polydipsia is excessive thirst or excess drinking.Porth, C. M. (1990). ''Pathophysiology: Concepts of altered health states''. Philadelphia: J.B. Lippincott Company. The word derives from the Greek () "very thirsty", which is derived from (, " ...
), low urine production ( oliguria), and bloody urine ( hematuria). Symptoms of ricin inhalation are different from those caused by ingestion. Early symptoms include a cough and fever. When skin or inhalation exposure occur, ricin can cause an
allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...
to develop. This is indicated by swelling (
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
) of the eyes and lips;
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
; bronchial irritation; dry, sore throat; congestion; skin redness ( erythema); skin blisters ( vesication);
wheezing A wheeze is a continuous, coarse, whistling sound produced in the respiratory airways during breathing. For wheezes to occur, some part of the respiratory tree must be narrowed or obstructed (for example narrowing of the lower respiratory tract ...
; itchy, watery eyes; chest tightness; and skin irritation.


Treatment

An antidote has been developed by the UK military, although as of 2006 it has not yet been tested on humans. As of 2005 another antidote developed by the US military has been shown to be safe and effective in lab mice injected with
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
-rich blood mixed with ricin, and has had some human testing. Symptomatic and supportive treatments are available for ricin poisoning. Existing treatments emphasize minimizing the effects of the poison. Possible treatments include
intravenous fluids Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutri ...
or electrolytes,
airway management Airway management includes a set of maneuvers and medical procedures performed to prevent and relieve airway obstruction. This ensures an open pathway for gas exchange between a patient's lungs and the atmosphere. This is accomplished by either cl ...
,
assisted ventilation Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move air i ...
, 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 "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...
or by performing
gastric lavage Gastric lavage, also commonly called stomach pumping or gastric irrigation, is the process of cleaning out the contents of the stomach. Since its first recorded use in early 19th century, it has become one of the most routine means of eliminating p ...
. Survivors often develop long-term organ damage. Ricin causes severe
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
and vomiting, and victims can die of
circulatory shock Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system. Initial symptoms of shock may include weakness, fast heart rate, fast breathing, sweating, anxiety, and increased t ...
or organ failure; inhaled ricin can cause fatal
pulmonary edema Pulmonary edema, also known as pulmonary congestion, is excessive liquid accumulation in the tissue and air spaces (usually alveoli) of the lungs. It leads to impaired gas exchange and may cause hypoxemia and respiratory failure. It is due ...
or respiratory failure. Death typically occurs within 3–5 days of exposure.


Prevention

Vaccination is possible by injecting an inactive form of protein chain A. 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.


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. The extracted oil is also heated to more than to denature any ricin that may be present. The remaining spent crushed seeds, called variously the "cake", "
oil cake A press cake or oil cake is the solids remaining after pressing something to extract the liquids. Their most common use is in animal feed. Some foods whose processing creates press cakes are olives for olive oil (''pomace''), peanuts for pea ...
", and "press cake", can contain up to 5% ricin. 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 autoclaving. Accidental ingestion of ''Ricinus communis'' cake intended for fertilizer has been reported to be responsible for fatal ricin poisoning in animals. Deaths from ingesting castor plant seeds are rare, partly because of their indigestible seed coat, and because some of the ricin is deactivated in the stomach. The pulp from eight beans is considered dangerous to an adult. Rauber and Heard have written that close examination of early 20th century
case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occur ...
s indicates that public and professional perceptions of ricin toxicity "do not accurately reflect the capabilities of modern medical management". 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%. In 2013 a 37-year-old woman in the United States survived after ingesting 30 beans. Victims often manifest
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
,
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin w ...
,
fast heart rate Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (s ...
, low blood pressure, and
seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with lo ...
s persisting for up to a week. Blood, plasma, or urine ricin or
ricinine Ricinine is a toxic alkaloid found in the castor plant. It can serve as a biomarker of ricin poisoning. It was first isolated from the castor seeds by Tuson in 1864. Ricinine has insecticidal effects. It sublimes between 170 and 180 °C at 20 m ...
concentrations may be measured to confirm diagnosis. The laboratory testing usually involves immunoassay or liquid chromatography-mass spectrometry.


Therapeutic applications

Although no approved therapeutics are currently based on ricin, it does have the potential to be used in the treatment of tumors, as a "magic bullet" to destroy targeted cells. Because ricin is a protein, it can be linked to a monoclonal antibody to target cancerous cells recognized by the antibody. The major problem with ricin is that its native 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 immunotoxins 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 Diphtheria toxin is an exotoxin secreted by ''Corynebacterium diphtheriae'', the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophageA prophage is a virus that has inserted itself into the genome of the h ...
, 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 In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
s into cells, thus greatly increasing their
immunogenicity Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted: * Wanted immunogenicity typically relates to vaccines, where the injectio ...
. Use of ricin as an
adjuvant In pharmacology, an adjuvant is a drug or other substance, or a combination of substances, that is used to increase the efficacy or potency of certain drugs. Specifically, the term can refer to: * Adjuvant therapy in cancer management * Analgesi ...
has potential implications for developing
mucosal A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It ...
vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.
s.


Regulation

In the US, ricin appears on the select agents list of the Department of Health and Human Services, and scientists must register with HHS to use ricin in their research. However, investigators possessing less than 1000 mg (1 g) are exempt from regulation. Ricin is classified as an 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.


Chemical or biological warfare agent

The United States investigated ricin for its military potential during World War I. At that time it was being considered for use either as a toxic dust or as a coating for bullets and shrapnel. The dust cloud concept could not be adequately developed, and the coated bullet/shrapnel concept would violate the
Hague Convention of 1899 The Hague Conventions of 1899 and 1907 are a series of international treaties and declarations negotiated at two international peace conferences at The Hague in the Netherlands. Along with the Geneva Conventions, the Hague Conventions were amon ...
(adopted in U.S. law at 32
Stat. The ''United States Statutes at Large'', commonly referred to as the ''Statutes at Large'' and abbreviated Stat., are an official record of Acts of Congress and concurrent resolutions passed by the United States Congress. Each act and resolutio ...
1903), specifically Annex §2, Ch.1, Article 23, stating "... it is especially prohibited ... employ poison or poisoned arms". World War I ended before the United States weaponized ricin. During World War II the United States and Canada undertook studying ricin in cluster bombs. 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 ( LCt50 ~10 mg/min·m3). Ricin was given the military symbol W or later WA. Interest in it continued for a short period after World War II, but soon subsided when the US Army Chemical Corps began a program to weaponize sarin. The Soviet Union also possessed weaponized ricin. The KGB developed weapons using ricin which were used outside the Soviet bloc, most famously in the Markov assassination. In spite of ricin's extreme
toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
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 and can be grown at home without any special care. Under both the 1972 Biological Weapons Convention and the 1997
Chemical Weapons Convention The Chemical Weapons Convention (CWC), officially the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, is an arms control treaty administered by the Organisation for ...
, ricin is listed as a schedule 1 controlled substance. Despite this, more than 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. 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 Anthrax is an infection caused by the bacterium '' Bacillus anthracis''. It can occur in four forms: skin, lungs, intestinal, and injection. Symptom onset occurs between one day and more than two months after the infection is contracted. The s ...
as biological weapons or chemical weapons, the quantity of ricin required to achieve LD50 over a large geographic area is significantly more than an agent such as anthrax (tons of ricin vs. only kilogram quantities of anthrax). Ricin is easy to produce, but is not as practical or likely to cause as many casualties as other agents. Ricin is easily denatured by temperatures over meaning many methods of deploying ricin would generate enough heat to denature it. 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. In contrast, anthrax
spore In biology, a spore is a unit of sexual or asexual reproduction that may be adapted for dispersal and for survival, often for extended periods of time, in unfavourable conditions. Spores form part of the life cycles of many plants, algae, ...
s may remain lethal for decades. Jan van Aken, a German expert on biological weapons, explained in a report for
The Sunshine Project The Sunshine Project was an international NGO dedicated to upholding prohibitions against biological warfare and, particularly, to preventing military abuse of biotechnology. It was directed by Edward Hammond. With offices in Austin, Texas, and H ...
that Al Qaeda's experiments with ricin suggest their inability to produce botulinum or anthrax.


Developments

A biopharmaceutical company called Soligenix, Inc. licensed an anti-ricin vaccine called RiVax from Vitetta et al. at
UT Southwestern The University of Texas Southwestern Medical Center (UT Southwestern or UTSW) is a public academic health science center in Dallas, Texas. With approximately 18,800 employees, more than 2,900 full-time faculty, and nearly 4 million outpatient ...
. The vaccine was found safe and immunogenic in mice, rabbits, and humans. Two successful clinical trials were completed. 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.


Synthesis

The first isolation of ricin is attributed to the Baltic-German microbiologist Peter Hermann Stillmark (1860–1923) in 1888.


Incidents

Ricin has been involved in a number of incidents. In 1978, the Bulgarian dissident Georgi Markov was assassinated by
Bulgarian secret police The Committee for State Security ( bg, Комитет за държавна сигурност, ''Komitet za darzhavna sigurnost''; abbreviated КДС, CSS, KDS), popularly known as State Security (Държавна сигурност, ''Darzhhav ...
who surreptitiously shot him on a London street with a modified umbrella using compressed gas to fire a tiny pellet contaminated with ricin into his leg. He died in a hospital a few days later and his body was passed to a special poison branch of the
British Ministry of Defence The Ministry of Defence (MOD or MoD) is the department responsible for implementing the defence policy set by His Majesty's Government, and is the headquarters of the British Armed Forces. The MOD states that its principal objectives are to d ...
that discovered the pellet during an autopsy. The prime suspects were the Bulgarian secret police: Georgi Markov had 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 have since confirmed the KGB's involvement. Earlier, Soviet dissident
Aleksandr Solzhenitsyn Aleksandr Isayevich Solzhenitsyn. (11 December 1918 – 3 August 2008) was a Russian novelist. One of the most famous Soviet dissidents, Solzhenitsyn was an outspoken critic of communism and helped to raise global awareness of political repr ...
also had (but survived) ricin-like symptoms after an encounter in 1971 with KGB agents. Ten days before the attack on Georgi Markov another Bulgarian defector,
Vladimir Kostov Vladimir may refer to: Names * Vladimir (name) for the Bulgarian, Croatian, Czech, Macedonian, Romanian, Russian, Serbian, Slovak and Slovenian spellings of a Slavic name * Uladzimir for the Belarusian version of the name * Volodymyr for the Ukra ...
, 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. Several terrorists and terrorist groups have experimented with ricin and caused several incidents of the poisons 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. Another was sent to the offices of Mayors Against Illegal Guns in Washington, D.C. A letter containing ricin was also alleged to have been sent to American President
Barack Obama Barack Hussein Obama II ( ; born August 4, 1961) is an American politician who served as the 44th president of the United States from 2009 to 2017. A member of the Democratic Party (United States), Democratic Party, Obama was the first Af ...
at the same time. An actress,
Shannon Richardson Shannon Guess Richardson (née Rogers; born August 31, 1977) is an American convicted felon and former actress. She worked in television and film roles, including '' The Walking Dead'', but is best known for sending ricin-laced letters to U.S. ...
, was later charged with the crime, to which she pleaded guilty that December. On 16 July 2014, Richardson was sentenced to 18 years in prison plus a restitution fine of $367,000. On 2 October 2018, two letters suspected of containing ricin were sent to
The Pentagon The Pentagon is the headquarters building of the United States Department of Defense. It was constructed on an accelerated schedule during World War II. As a symbol of the U.S. military, the phrase ''The Pentagon'' is often used as a metony ...
; one addressed to Secretary of Defense James Mattis, and the other to Chief of Naval Operations, Admiral John Richardson. 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. In 2020, some media in the
Czech Republic The Czech Republic, or simply Czechia, is a landlocked country in Central Europe. Historically known as Bohemia, it is bordered by Austria to the south, Germany to the west, Poland to the northeast, and Slovakia to the southeast. The ...
reported (based on intelligence information) that a person carrying a Russian diplomatic passport and ricin had arrived in Prague with an intention to assassinate three politicians, however
Vladimir Putin Vladimir Vladimirovich Putin; (born 7 October 1952) is a Russian politician and former intelligence officer who holds the office of president of Russia. Putin has served continuously as president or prime minister since 1999: as prime min ...
, the president of Russia, called it fake. The targets would have been: first, Zdeněk Hřib, the mayor of
Prague Prague ( ; cs, Praha ; german: Prag, ; la, Praga) is the capital and largest city in the Czech Republic, and the historical capital of Bohemia. On the Vltava river, Prague is home to about 1.3 million people. The city has a temperate ...
(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 Boris Yefimovich Nemtsov ( rus, Бори́с Ефи́мович Немцо́в, p=bɐˈrʲis jɪˈfʲiməvʲɪtɕ nʲɪmˈtsof; 9 October 195927 February 2015) was a Russian physicist and liberal politician. He was involved in the introduction ...
, an opposition politician assassinated in the Kremlin in 2015. Second, Ondřej Kolář, the mayor of Prague 6 municipal district, who was involved in removing the controversial statue to the Soviet-era
Marshal Konev Ivan Stepanovich Konev ( rus, link=no, Ива́н Степа́нович Ко́нев, p=ɪˈvan sʲtʲɪˈpanəvʲɪtɕ ˈkonʲɪf;  – 21 May 1973) was a Soviet general and Marshal of the Soviet Union who led Red Army forces on the ...
. Third, Pavel Novotný, the mayor of Prague's southwestern Řeporyje district. All of these three politicians had received police protection. Later, the Czech president Miloš Zeman claimed that the police protection of Zdeněk Hřib is a publicity stunt. Zeman also confused ricin with castor oil and claimed that ricin is a non-poisonous laxative.


In popular culture

Ricin has been used as a plot device, such as in the television series ''
Breaking Bad ''Breaking Bad'' is an American crime drama television series created and produced by Vince Gilligan. Set and filmed in Albuquerque, New Mexico, the series follows Walter White (Bryan Cranston), an underpaid, overqualified, and dispirited h ...
''. 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. Daniel Milzman, a 19-year-old former
Georgetown University Georgetown University is a private research university in the Georgetown neighborhood of Washington, D.C. Founded by Bishop John Carroll in 1789 as Georgetown College, the university has grown to comprise eleven undergraduate and graduate ...
student, was charged with manufacturing ricin in his dorm room, as well as the intent of "
sing Singing is the act of creating musical sounds with the voice. A person who sings is called a singer, artist or vocalist (in jazz and/or popular music). Singers perform music (arias, recitatives, songs, etc.) that can be sung with or without ...
the ricin on another undergraduate student with whom he had a relationship". Mohammed Ali from
Liverpool Liverpool is a City status in the United Kingdom, city and metropolitan borough in Merseyside, England. With a population of in 2019, it is the List of English districts by population, 10th largest English district by population and its E ...
, England, was convicted after attempting to purchase 500 mg of ricin over the
dark web The dark web is the World Wide Web content that exists on ''darknets'': overlay networks that use the Internet but require specific software, configurations, or authorization to access. Through the dark web, private computer networks can comm ...
from an undercover FBI agent. He was sentenced, on 18 September 2015, to eight years imprisonment. In the 2013 movie ''The Good Mother'', antagonist Cheryl Jordan injects her daughters with ricin and puts ricin in their food in order to poison them in a case of
Munchausen by proxy Factitious disorder imposed on another (FDIA), also known as fabricated or induced illness by carers (FII), and first named as Munchausen syndrome by proxy (MSbP), is a condition in which a caregiver creates the appearance of health problems in a ...
. She is eventually caught after one daughter dies.


See also

* '' Viscum album'' (European mistletoe)


References


External links


Studies showing lack of toxicity of castor oil
from the US Public Health Service
Castor bean information
at
Purdue University Purdue University is a public land-grant research university in West Lafayette, Indiana, and the flagship campus of the Purdue University system. The university was founded in 1869 after Lafayette businessman John Purdue donated land and ...

Plants Poisonous to Livestock
– Ricin information at
Cornell University Cornell University is a private statutory land-grant research university based in Ithaca, New York. It is a member of the Ivy League. Founded in 1865 by Ezra Cornell and Andrew Dickson White, Cornell was founded with the intention to tea ...

Ricin cancer therapy tested
at BBC
Ricin – Emergency Preparations
at
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...

Emergency Response Card – Ricin
at
CDC The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...
* {{Authority control Biological toxin weapons Castor oil plant Lectins Legume lectins Plant toxins Proteins Ribosome-inactivating proteins Toxins