Ricin: History, Origins, Toxicity and Properties
|✅ Paper Type: Free Essay||✅ Subject: Biology|
|✅ Wordcount: 1650 words||✅ Published: 18th May 2018|
ORIGIN OF RICIN
Ricin is a protein extracted from the seeds of the castor bean plant (Ricinus communis). Ricin is a lectin and a member of a group of ribosome-inactivating proteins like abrin (from the seeds of the rosary pea, Abrus precatorius), that prevent synthesis of protein in eukaryotic ribosomes. Ricin is one of the most toxic substances and as such was once known to be a chemical weapon (Agent W) but is now subject to the Chemical Weapons Convention. However, ricin has been used as a poison for criminal and terrorist purposes.
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Ricin is an extremely toxic poison, and thus can kill even if applied in a small amount. Thus, the introduction of rapid, highly sensitive chemical and biological/immunological analytical methods capable of detecting the toxin at or below ng/ml level is of vital importance (see, for example, Kalb and Barr, 2009; Lubelli et al., 2006; Uzawa et al., 2008). In cases where castor beans or crude ricin preparations are the possibly dangerous poisons, ricinine can also serve as a biomarker (see, for example, Mouser et al., 2007).
The chemical is particularly deadly because it can be inhaled, ingested, or swallowed and is quickly broken down in the body and is virtually undetectable. There is currently no antidote to ricin, although a prospective vaccine has been developed that has been successfully tested in mice. Ricin is a potent protein cytotoxin derived from the beans of the castor plant. Castor beans are omnipresent worldwide, and the toxin is fairly easy to extract; therefore, ricin is widely available. Ricin’s significance as a potential BW [biological warfare] toxin relates in part to its wide availability.
HOW IT IS OBTAINED
Ricin toxin, found in the bean of the castor plant, Ricinis communis, is one of the most toxic and easily produced plant toxins. The shrub like ornamental castor plant, Ricinus communis (Euphorbiaceae), originated in Africa and Asia, and has been cultivated and distributed throughout the world. The annual production of castor oil seed exceeds over 1 million metric tonnes (Food and Agricultural Organization of the United Nations, 2009). Ricin is a byproduct of castor oil production: when castor beans are crushed, they form a pulp from which castor oil is extracted, and ricin is what remains. The waste mash from this process is 3-5% ricin by weight. The seeds of the plant have three main constituents: oil, castor oil, which is the glyceride of ricinoleic acid; a mildly toxic alkaloid ricinine and several isoforms of a highly poisonous glycoprotein ricin present up to 5% in the seeds.
Although adaptable to a wide temperature range, it fails to resist to subfreezing temperatures and withstand best in elevated year-round temperatures. Brazil, Ecuador, Ethiopia, Haiti, India, and Thailand are the countries which commercially cultivate most of the seeds. Castor oil is found in many commonly used substances such as paints, varnishes, and lubricating oils, and is also used as a purgative. After oil isolation, the remaining seed cake may be detoxified by heat treatment and used as an animal feed supplement. The seed hulls are similar to barnyard manure in their fertilizer value. The toxicity of castor beans has been known since ancient times and more than 750 cases of intoxication in humans have been described. Although ricin’s lethal toxicity is approximately 1,000-fold less than that of botulinum toxin, ricin may have significance as a biological weapon because of its heat stability and worldwide availability, in massive quantities, as a by-product of castor oil production.
DESCRIPTION OF THE AGENT
Identity and Physicochemical Properties
Ricin is a 66-kilodalton (kd) globular protein that makes up 1% to 5% by weight of the bean of the castor plant, Ricinis communis. The CAS Registry Number of ricin is [9009-86-3]. In a pure state, ricin is a white crystalline powder. It is a water-soluble glycoprotein consisting of two polypeptides, termed A and B chains, which are linked by a disulfide bond (ASSB). The amino acid sequence of ricin (or ricin D as the toxic fraction from the beans is called) was resolute by Funatsu et al. (1978, 1979).
The A chain contains 265 amino acids and has a molecular weight of 32 kDa; its sugar content is 2.6%. The isoelectric point of the A chain is 7.34. The B chain of 260 amino acids and four internal disulfide bonds has a molecular weight of 34 kDa and its sugar content is 6.4%. The A chain has enzymatic properties (ribosomal RNA N-glycosidase, EC 184.108.40.206) responsible for the toxicity of ricin, while the B chain is a lectin binding to galactose-containing glycoproteins and glycolipids on the surface of target cell components. The use of X-ray crystallography studies was used to solve the three-dimensional structure of ricin (reviewed by Lord et al., 1994). The physicochemical and photochemical properties of ricin have recently been assessed (Gaigalas et al., 2007).
Because the chaff left over from castor oil processing can be used to feed cattle, a great deal of effort was dedicated to its detoxification (Balint, 1974; European Food Safety Authority, 2008). High-temperature denaturing (>80°C for 1 h) and chemical methods (oxidation with potassium permanganate, hydrogen peroxide, iodine, etc.) were put forward to destroy the toxin (see, for example, Barnes et al., 2009). In the presence of 2-mercaptoethanol, which reduces the disulfide bond joining the A and B chains, the toxicity of ricin is lost; removal of 2-mercaptoethanol, however, allows the reconstitution and reactivation of the toxin. Ricin is degraded by papain but only slowly by trypsin. The fate of ricin in the body is incompletely understood.
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The toxin-rich chaff byproduct of castor oil manufacture has been used to kill mice and moles. Conjugates of ricin and cell-specific antibodies are experimental anticancer immunochemotherapeutic agents (Sandvig and van Deurs, 2005; Stirpe et al., 1992). Recently, transgenic rice and maize engineered to produce a fusion protein comprising the Cry1Ac endotoxin of Bt and the ricin B lectin subunit have proved to be insecticidal to insects that are otherwise able to endure Cry toxins (Mehlo et al., 2005).
Mode of action
Once it was thought that the toxic action of ricin preparations in mammals is due to its hemagglutinating effect, but this activity was shown to be associated with the structurally similar, but nontoxic agglutinins present in the castor bean. It is now well established that ricin inhibits protein synthesis in eukaryotic systems by catalytically inactivating the 60S subunit involved in the translation process. The structural aspects of biochemical interaction of ricin and other ribosome-inactivating protein (RIP) toxins from plants and fungi were entirely assessed (Kozlov et al., 2006; Stirpe and Battelli, 2006).
Briefly, the B chain binds to galactose/N-acetylgalactosamine-containing glycoproteins and glycolipids in eukaryotic cells. The binding to surface receptors can be inhibited by galactose or lactose in vitro. It appears that both chains facilitate the penetration by endocytosis of the toxin into the cell. The B chain, however, aids the toxin in translocating to endosomal targets as well. Once in the cytosol, the A chain cleaves a single adenine base from the 28S ribosomal (Ribonucleic acid) RNA within the 60S ribosomal subunit, rendering it unable to bind the elongation factor 2 which consequently leads to an arrest of protein synthesis. A single A chain molecule can inactivate 1500 ribosomes per minute and kill the cell. In addition to inhibiting protein synthesis, ricin was shown to provoke apoptosis, cause oxidative stress, release proinflammatory cytokines, modify cell membrane structure and function, and impair nuclear DNA (reviewed by Stirpe and Battelli, 2006). Lipase activity of ricin was also clearly shown (Morlon-Guyot et al., 2003).
Toxicity to Laboratory Animals
Although the mode of action of ricin at the molecular level is known, the mechanisms responsible for the clinical and lethal effects of the toxin are still inadequately understood. Representative animal toxicity data for ricin administered by different routes are shown in Table 1. The variations in the acute toxicity values reported in the literature are mainly due to mixture of the preparations used in the tests (reviewed by Balint, 1974). The symptoms of ricin poisoning manifest slowly, usually 12 hr after administration, and include rather sudden outbursts of convulsions and opisthotonos, followed by paralysis of the respiratory center, eventually leading to death. Fortuitous poisoning is usually due to ingestion of castor beans (for recent examples, see Aslani et al., 2007; Soto-Blanco et al., 2002). Laboratory tests with seeds showed hen to be the most resistant species (the lethal dose was 14 g/kg); sheep and horse were more sensitive (lethal doses were 1.25 and 0.10 g/kg, respectively). The toxin is pyrogenic in mammals (Balint, 1993). In the serum of animals treated with ricin, antibodies specific to ricin have repeatedly been detected (see, for example, Griffiths et al., 2007).
Ricin is highly toxic upon injection and inhalation. Using transmission electron microscopy, Brown and White (1997) (see also Griffiths et al., 1995b, 2007) examined the histopathological changes in the lungs of rats upon ricin inhalation. The animals were exposed to an LCt30 (the concentration in air that killed 30% of the exposed animals) of 11.21 mg/min/m3 dose of the toxin. Necrotic changes were evident in the capillary endothelium and type I epithelial cells, accompanied by intraalveolar edema 12-15 h after exposure.
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