Chiara Pastura
Isabella Ragona
What We Still Don’t Know About the Ricin
Ricin is a "highly toxic, naturally occurring lectin (a carbohydrate-binding protein) produced in the seeds of the castor oil plant Ricinus communis " Wikipedia ; the seeds can be crushed in an oil press to extract castor oil. It is a stable substance under normal conditions, but can be inactivated by heat above 80 degrees centigrade.
A dose the size of a few grains of table salt can kill an adult human; the median lethal dose of ricin is around 22 micrograms per kilogram in humans if exposure is from injection or inhalation. Oral exposure to ricin is far less toxic and a lethal dose can be up to 30–40 milligrams per kilogram.
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. Both type 1 and type 2 RIPs are functionally active against ribosomes in vitro, however only type 2 RIPs display cytoxicity due to the lectin-like properties of the B chain. In order to display its ribosome-inactivating function, the ricin disulfide bond must be reductively cleaved.
Structure
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 A chain (RTA) is an N-glycoside hydrolase 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 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. At least one of these three subdomains in each homologous lobe possesses a sugar-binding pocket that gives RTB its functional character.
Many plants such as barley have the A chain but not the B chain. People do not get sick from eating large amounts of such foods, as ricin A is of extremely low toxicity as long as the B chain is not present.
Ricin Toxin from Castor Bean Plant, Ricinus communis. 2014
Ribosome inactivation
RTA has rRNA N-glycosylase activity that is responsible for the cleavage of a glycosidic bond within the large rRNA of the 60S subunit of eukaryotic ribosomes. RTA specifically and irreversibly hydrolyses the N-glycosidic bond of the adenine residue within the 28S rRNA, but leaves the phosphodiester backbone of the RNA intact. The ricin targets is contained in a highly conserved sequence of 12 nucleotides universally found in eukaryotic ribosomes. The sequence, 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.
Ricin: structure, mode of action, and some current applications. 1994
Toxicity
Ricin is poisonous if inhaled, injected, or ingested; it acts as a toxin by inhibiting protein synthesis. It prevents cells from assembling various amino acids 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. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract, where it may cause mucosal injuries.
Because the symptoms are caused by failure to make protein, they emerge only after a variable delay from a few hours to a full day after exposure.
Deaths from ingesting castor plant seeds are rare, partly because of their indigestible capsule, and because the body can, although only with difficulty, digest ricin. The pulp from eight beans is considered dangerous to an adult.
Overdose
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.
Signs and symptoms of ricin exposure
The major symptoms of ricin poisoning depend on the route of exposure and the dose received, though many organs may be affected in severe cases. Initial symptoms of ricin poisoning by inhalation may occur as early as 4- 8 hours and as late as 24 hours after exposure. Following ingestion of ricin, initial symptoms typically occur in less than 10 hours.
- Inhalation: Within a few hours of inhaling significant amounts of ricin, the likely symptoms would be respiratory distress (difficulty breathing), fever, cough, nausea, and tightness in the chest. Heavy sweating may follow as well as fluid building up in the lungs (pulmonary edema). This would make breathing even more difficult, and the skin might turn blue. Excess fluid in the lungs would be diagnosed by x-ray or by listening to the chest with a stethoscope. Finally, low blood pressure and respiratory failure may occur, leading to death.
- Ingestion: If someone swallows a significant amount of ricin, he or she would likely develop vomiting and diarrhea that may become bloody. Severe dehydration may be the result, followed by low blood pressure. Other signs or symptoms may include seizures, and blood in the urine. Within several days, the person's liver, spleen, and kidneys might stop working, and the person could die.
- Skin and eye exposure: Ricin is unlikely to be absorbed through normal skin. Contact with ricin powders or products may cause redness and pain of the skin and the eyes. However, if you touch ricin that is on your skin and then eat food with your hands or put your hands in your mouth, you may ingest some.
Emergency Preparedness and Response: facts about ricin. 2013
Death from ricin poisoning could take place within 36 to 72 hours of exposure, depending on the route of exposure (inhalation, ingestion, or injection) and the dose received.
Treatments
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.
Symptomatic and supportive treatments are available. The types of supportive medical care would depend on several factors, such as the route by which victims were poisoned (that is, whether poisoning was by inhalation, ingestion, or skin or eye exposure). Care could include such measures as helping victims breathe, giving them intravenous fluids (fluids given through a needle inserted into a vein), giving them medications to treat conditions such as seizure and low blood pressure, flushing their stomachs with activated charcoal (if the ricin has been very recently ingested), or washing out their eyes with water if their eyes are irritated.
Therapeutic applications
Ricins have the potential to be used in the treatment of tumors to destroy targeted cells. Because ricin is a protein, it can be linked to a monoclonal antibody to target malignant 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 then the drug will be internalized by, and kill, untargeted non-tumorous cells as well as targeted malignant 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, have proven to be more practical. No approved therapeutics are currently based on ricin. A promising approach is also to use the non-toxic B subunit (a lectin) as a vehicle for delivering antigens into cells, thus greatly increasing their immunogenicity. Use of ricin as an adjuvant has potential implications for developing mucosal vaccines.
Ricin cancer therapy tested. 2003
