Ricinus Communis

The Ricin is a toxin derived from the castor bean plant Ricinus communis. It is composed of two 33-kd subchains, A and B linked by a disulfide bond and operates by modifying ribosomes thus blocking protein synthesis.[1,21] Ricin is highly toxic, though not as toxic as botulinum toxin, and easily produced. Its worldwide availability and heat stability make Ricin a possible biological weapon.

The ricin toxin was discovered in the late 1880’s by Stillmark, [4] which he named ricin. Paul Ehrlich studied ricin [6] during the 1890’s; work which would become the very foundation of the science of immunology. Native ricin was first shown to inhibit tumor grown in 1951 [8] and has recently gained acceptance as an immunotoxin [9] or antitumor agent. Ricin was used in the highly publicized assassination of Bulgarian defector Georgi Markov. [16]

 

Organism Features
Popular name Ricin, Ricin toxin
Scientific name (binomial name) Ricinus communis
Taxonomy/Phylogeny
Kingdom Plantae [1]
Subkingdom Trachebiotna
Phylum (Division) Magnololphyta
Subphylum
Superclass
Class Magnoliopsida
Subclass Rosidae
Order Euphorbiales
Family Euphorbiaceae
Genus Ricinus
Species communis
Morphology
Cyst (Dormant) N/A
Trophozoite (Active) N/A
Life cycle N/A
Pathogenic
Non-Pathogenic
Reproduction N/A
Metabolism
Related organisms
Host(s) N/A
Data
Genomic Data
Sequencing Status

Sequencing Institution

Coverage

Status

Date

Accession Number

Strain

Length (in base pairs)

Number of ORFs

GC Content

No. Of Chromosomes

Annotation Data
Virulence factors
Polymorphisms/variable antigens
Proteomic data
Epitope data
Structural Ricin, which consists of two subunits, A & B linked by a disulfide bond, has been crystallized and characterized. [22,23]
Gene expression data
Animal Model data
Clinical features The clinical symptoms of ricin toxicity vary according to the dose and the route of exposure.[38] Animal experiments suggest that clinical signs and pathologies are route specific; for example ingestion induces gastrointestinal signs and gastrointestinal hemorrhage with necrosis of the liver, spleen and kidneys; intramuscular intoxication causes severe localized pain, muscle and regional lymph node necrosis, and moderate involvement of visceral organs and inhalation results in respiratory distress and airway and pulmonary lesions.
Disease
Infectious dose Ricin infectious doses in mice. [56]

Route LD 50 (µg/kg) Time to Death (hrs)
Inhalation 3 to 5 60
Intravenous injection 5 90
Interperitoneal injection 22 100
Subcutaneous injection 24 100
Intragastric 20 (mg/kg) 85
Prevalence by region / Geographic distribution
Infectivity rate

Death rate

Transmission

Epidemiology

Outbreaks

Symptoms and Signs 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.

  • Inhalation

Clinical data on inhalation exposure is not available for humans however rat inhalation exposure data shows necrotizing pneumonia of the airways with interstitial and alveolar inflammation and edema.[42]

  • Ingestion

Ricin is less toxic by ingestion than by other routes. [56] A. Rauber and J. Heard researched 751 cases of castor bean ingestion [2] over the course of many decades in which they documented 14 fatalities for an effective death rate of 1.9%. All of the serious or fatal cases of persons who ingested castor beans exhibited similar signs including rapid onset of nausea, vomiting and abdominal pain followed by diarrhea; hemorrhage from the anus; anuria; cramps; dilation of the pupils; fever; thirst; sore throat; headache; vascular collapse; and shock. Death occurred on the third day or later.

  • Injection

Low doses of 18-20 µg/m 2 have been shown to be tolerated in a large clinical trail of cancer patients [40]. Flu like symptoms with fatigue was observed in many as well as some nausea and vomiting. These symptoms began 4 to 6 hours after administration and lasted for 1 to 2 days.

In the most famous case of injection, the assassination of Georgi Markov [16], whose was assassinated with an injection of a lethal dose of ricin, estimated to be as much as 500 µg, resulted in almost immediate local pain, then a feeling of weakness within about 5 hours. Fifteen to 24 hours later, he had a high temperature, nausea, and vomiting. Thirty-six hours after the incident, Mr. Markov was admitted to the hospital feeling very ill with a fever, tachycardia, and normal blood pressure; his lymph nodes in the affected groin were swollen and sore; and a 6-cm diameter area of induration and inflammation was observed at the injection site on his thigh. Two days after the attack, he became suddenly hypotensive and tachycardic; with a pulse rate of 160 beats per minute, and vascular collapse and shock had set in. His white blood count was 26,300/mm 3. Early on the third day after the attack, he became anuric and began vomiting blood. An electrocardiogram demonstrated complete atrioventricular conduction block. Mr. Markov died shortly thereafter; at the time of death, his white blood count was 33,200/mm 3.

Pathogenesis
Target organs Organs targeted by ricin include: liver, spleen and kidneys (ingestion), lungs, throat (inhalation) and localized muscles and regional lymph nodes (intramuscular) [38]
Risk factors
Diagnosis
Duration
Organisms with similar etiology
Therapy
Prognosis
Prevention
Vaccinology A vaccine for ricin has been developed and tested in mice by mutating the active site of the A subchain of the toxin. [57]
Immune response
Information resources
References
[1] Retrieved October 13, 2004, from the ITIS website:

 

  • Relevant Links
  1. Medical Aspects of Chemical and Biological Warfare , Chapter 32, Ricin Toxin:
  • Relevant publications (Publication source: Franz, DR, Jaax, NJ. [56])
    1. Barbieri L, Baltelli M, Stirpe F. Ribosomes-inactivating proteins from plants. Biochemica Biophysica Acta. 1993; 1154:237–282.
    2. Rauber A, Heard J. Castor bean toxicity re-examined: A new perspective. Vet Hum Toxicol . 1985;27: 498–502.
    3. Wannemacher R, Hewetson J, Lemley P, et al. Comparison of detection of ricin in castor bean extracts by bioassays, immunoassays, and chemistry procedures. In: Gopalakrishnakone P, Tan C, eds. Recent Advances in Toxinology Research . Singapore: National University of Singapore; 1992: 108–119.
    4. Stillmark. Ueber Ricen. Arbeiten des Pharmacologischen Institutes zu Dorpat, iii, 1889. Cited in: Flexner J. The histological changes produced by ricin and abrin intoxications. J Exp Med. 1897;2:197–216.
    5. Sharon N, Lis H. Cell-agglutinating and sugar-specific proteins. Science. 1972;177:949–959.
    6. Ehrlich P. Experimentelle Untersuchungen über Immunität, I: Euber Ricin. Deutsch Med Wochenschr. 1891;17:976–979.
    7. Ehrlich P. Experimentelle Untersuchungen über Immunität, II: Euber Abrin. Deutsch Med Wochenschr. 1891;17:1218–1219.
    8. Olsnes S, Pihl A. Abrin, ricin, and their associated agglutinins. In: Cuatrecasas P, ed. Receptors and Recognition: The Specificity and Action of Animal, Bacterial, and Plant Toxins . London, England: Chapman and Hall; 1976: 129–173.
    9. Olsnes S, Pihl A. Construction and properties of chimeric toxins target specific cytotoxic agents. In: Dorner F, Drews J, eds. Pharmacology of Bacterial Toxins. New York, NY: Pergamon Press; 1986: 709-739.
    10. Magerstadt M. Therapeutic aminoconjugates. In: Antibody Conjugates and Malignant Disease. Boca Raton, Fla: CRC Press; 1991: Chap 3.
    11. Ucken F, Frankel A. The current status of immunotoxins: An overview of experimental and clinical studies as presented at the 3rd International Symposium on Immunotoxins. Leukemia. 1993;7:341–348.
    12. Vitetta E, Thorpe P, Uhr J. Immunotoxins: Magic bullets or misguided missiles? Trends Pharmacol Sci. 1993;14(5):148–154.
    13. Vitetta E, Krolick K, Muneo M, Cushley W, Uhr J. Immunotoxins: A new approach to cancer therapy. Science. 1983;219:644–649.
    14. Thorpe PE, Mason DW, Brown AN, et al. Selective killing of malignant cells in leukemic rat bone marrow using an antibody–ricin conjugate. Nature. 1982; 297:594–596.
    15. Cookson J, Nottingham J. A Survey of Chemical and Biological Warfare. New York, NY: Monthly Review Press. 1969: 6.
    16. Crompton R, Gall D. Georgi Markov: Death in a pellet. Med Leg J. 1980;48:51–62.
    17. Sharn L. Probe aims at sale of deadly bacteria. USA Today. 11 Jul 1995;2-A.
    18. Kifner J. Man is arrested in a case involving deadly poison. New York Times. 23 Dec 1995;A-7.
    19. Goodman PS. Seized poison set off few alarms. Anchorage Daily News. 4 Jan 1996;B-1.
    20. Nelan BW. The price of fanaticism. Time. 3 Apr 1995;38–41.
    21. Robertus J. Toxin structure. In: Frankel A, ed. Immunotoxins. Boston, Mass: Kluwer Academic Publishers; 1988: 11–24.
    22. Youle R, Huang A. Protein bodies from the endosperm of castor beans, subfractionation, protein components, lectins, and changes during germination. Plant Physiol. 1976;58:703.
    23. Rutenber E, Katzin B, Collins E, et al. The crystallographic refinement of ricin at 2.5 Å resolution. Proteins. 1991; 10:240–250.
    24. Wales R, Richardson PT, Roberts LM, Woodland HR, Lord JM. Mutational analysis of the galactose binding ability of recombinant ricin B chain. J Biol Chem. 1991;266(29):19172–19179.
    25. Afrin LB, Gulick H, Vesely J, Willingham M, Frankel AE. Expression of oligohistidine-tagged ricin B chain in Spodoptera frugiperda . Bioconjug Chem. 1994;5(6):539–546.
    26. Frankel A, Roberts H, Afrin L, Vesely J, Willingham M. Expression of ricin B chain in Spodoptera frugiperda. Biochem J . 1994;303(pt 3):787–794.
    27. Robertus J, Piatak M, Ferris R, Houston L. Crystallization of ricin A chain obtained from a cloned gene expressed in Escherichia coli. J Biol Chem. 1987; 262:19–20.
    28. Balint GA. Ricin: The toxic protein of castor oil seeds. Toxicology. 1974;2(1):77–102.
    29. Wannemaker R. Assistant Division Chief, Toxinology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, September 1994.
    30. Ghosh P, Wellner R, Cragoe E, Wu H. Enhacement of ricin cytotoxicity in Chinese hamster ovary cells by depletion of intracellular K+: Evidence for Na+/H+ exchange system in Chinese hamster ovary cells. J Cell Biol. 1985; 101:350–357.
    31. Moya M, Dautry-Varsat A, Goud B, Louvard D, Boquet P. Inhibition of coated pit formation in Hep2 cells blocks the cytotoxicity of diptheria toxin but not that of ricin toxin. J Cell Biol. 1985;101(2):548–559.
    32. Sandvig K, Olsnes S, Pihl A. Kinetics of binding of the toxic lectins abrin and ricin to surface receptors of human cells. J Biol Chem. 1976;251(13):3977–3984.
    33. Lord JM, Roberts LM, Robertus JD. Ricin: Structure, mode of action, and some current applications. FASEB J. 1994;8:201–208.
    34. Hudson T, Neville D. Temporal separation of protein toxin translocation from processing events. J Biol Chem. 1987;262:16484–16494.
    35. Youle R, Neville D. Kinetics of protein synthesis inactivation by ricin-anti-thy.1.1 monoclonal antibody hybrids: Role of the ricin B subunit demonstrated by reconstitution. J Biol Chem. 1982;267:1598–1601.
    36. Endo Y, Mitsui K, Motizuki M, Tsurugi K. The mechanism of action of ricin and related toxic lectins on eukaryotic ribosomes: The site and the characteristics of the modification in 28S ribosomal RNA caused by the toxins. J Biol Chem . 1987;262(12):5908–5912.
    37. Olsnes S. Closing in on ricin action. Nature . 1987;328:474–475.
    38. Olsnes S, Pihl A. Toxic lectins and related proteins. In: Cohen P, van Heyningen S, eds. Molecular Action of Toxins and Viruses . Amsterdam, Netherlands: Elsevier Biomedical Press; 1982: 51–105.
    39. Zenilman ME, Fiani M, Stahl P, Brunt E, Flye MW. Use of ricin A-chain to selectively deplete Kupffer cells. J Surg Res . 1988;45(1):82–89.
    40. Fodstad O, Kvalheim G, Godal A, et al. Phase I study of the plant protein ricin. Cancer Res. 1984;44:862–865.
    41. Brugsch HG. Toxic hazards: The castor bean. Mass Med Soc. 1960;262:1039–1040.
    42. Assaad A. Principal Investigator, Aerobiology and Product Evaluation Department, Toxinology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, December 1994.
    43. Davis K. Lieutenant Colonel, Veterinary Corps, US Army. Chief, Experimental Pathology Department, Pathology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, July 1994.
    44. Wilhelmsen C, Pitt L. Lesions of acute inhaled lethal ricin intoxication in rhesus monkeys. Vet Pathol. 1993;30:482.
    45. Soler-Rodriguez A, Ghetie M, Oppenheimer-Marks N, Uhr J, Vitetta E. Ricin A-chain and ricin A-chain immunotoxins rapidly damage human endothelial cells: Implications for vascular leak syndrome. Experimental Cell Research . 1993;206:227–234.
    46. Howat AJ. The toxic plant proteins ricin and abrin induce apoptotic changes in mammalian lymphoid tissues and intestine. J Pathol. 1988;154:29–33.
    47. Bingen A, Creppy EE, Gut JP, Dirheimer G, Kirn A. The Kupffer cell is the first target in ricin-induced hepatitis. J Submicrosc Cytol . 1987; 19(2):247-256.
    48. Derenzini M, Bonetti E, Marionozzi V, Stirpe F. Toxic effects of ricin: Studies on the pathogenesis of liver lesions. Virchows Arch B Cell Pathol . 1976; 20:15–28.
    49. Hewetson J. Principal Investigator, Immunology and Molecular Biology Department, Toxinology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Md. Personal communication, June 1994.
    50. Poli MA, Rivera VR, Hewetson JF, Merrill GA. Detection of ricin by colorimetric and chemiluminescence ELISA. Toxicon . 1994; 32(11):1371–1377.
    51. Ramsden C, Drayson M, Bell E. The toxicity, distribution, and excretion of ricin holotoxin in rats. Toxicology. 1989; 55:161–171.
    52. Hewetson J, Rivera V, Lemley P, Pitt M, Creasia D, Thompson W. A formalinized toxoid for protection of mice from inhaled ricin. Vaccine Research. 1996; 4:179–187.
    53. Yan C, Resau JH, Hewetson J, West M, Rill W, Kende M. Characterization and morphological analysis of protein-loaded poly(lactide-co-glycolide) microparticles prepared by water-in-oil-in-water emulsion technique. Journal of Controlled Release . 1994; 32:231–241.
    54. Poli M, Virera V, Pitt L, Vogel P. Aerosolized specific antibody protects mice from lung injury associated with aerosolized ricin exposure. In: 11th World Congress on Animal, Plant, and Microbial Toxins; 1994; Tel Aviv, Israel. Abstract.
    55. Thompson W, Scovill J, Pace J. Drugs that show protective effects from ricin toxicity in in-vitro protein synthesis assays. Natural Toxins. 1995;3:369–377.
    56. David R. Franz and Nancy K. Jaax, “Ricin Toxin”, Medical Aspects of Chemical and Biological Warfare, (Washington, DC: Borden Institute, Walter Reed Army Medical Center) 1997, Chapter 32, pp. 631-642.
    57. Joan E. Smallshaw, Ana Firan, John R. Fulmer, Stephen L. Ruback, Victor Ghetie and Ellen S. Vitetta A novel recombinant vaccine which protects mice against ricin intoxication.Vaccine, Volume 20, Issues 27-28, 10 September 2002, Pages 3422-3427.