ABSTRACT
I. Introduction.......................................................................................................................... 424 A. Introduction to Human Health Effects......................................................................... 425 B. Biological Warfare and Terrorism ............................................................................... 425
II. Overview of Ribosome-Inactivating Proteins...................................................................... 426 A. Type 1 RIPs ................................................................................................................. 427 B. Type 2 RIPs ................................................................................................................. 427 C. Type 3 RIPs ................................................................................................................. 427
III. Biochemistry and Pathophysiology of Ricin....................................................................... 428 A. Cell Binding and Internalization.................................................................................. 428 B. Intracellular Trafficking ............................................................................................... 429
1. Retrotranslocation to the Cytosol ......................................................................... 429 2. Role of Target Cell ERAD Pathway .................................................................... 429
C. Catalytic Inactivation of Ribosomes............................................................................ 430 1. RTA Structure and Function................................................................................. 430 2. Inhibition of Target Cell Translation .................................................................... 431
D. Secondary Catalytic Activities..................................................................................... 431 1. Polynucleotide Substrates ..................................................................................... 431 2. Lipid Substrates..................................................................................................... 431
IV. Cytotoxicity of Ricin ........................................................................................................... 432 A. Importance of Protein Synthesis Inhibition ................................................................. 432 B. Comparison with Related Plant Toxins ....................................................................... 433 C. Role of Apoptosis ........................................................................................................ 433
V. Effects of Ricin on Laboratory Animals ............................................................................. 434 A. Injected Ricin ............................................................................................................... 434 B. Biodistribution ............................................................................................................. 436 C. Inhalation Toxicity....................................................................................................... 436 D. Gastrointestinal Toxicity.............................................................................................. 437 E. Ocular Toxicity ............................................................................................................ 438 F. Comparisons among Related Plant Toxins.................................................................. 438 G. Sublethal Exposure ...................................................................................................... 438 H. Toxicity of Isolated A-Chain ....................................................................................... 439 I. Synthetic and Chimeric Toxins ................................................................................... 439
VI. Effects of Ricin on Humans ................................................................................................ 440 A. Castor Seed Ingestion .................................................................................................. 440
B. Castor Seed Allergy .................................................................................................. 442 C. Inhalation Toxicity .................................................................................................... 442 D. Injected Ricin ............................................................................................................ 443 E. Sublethal Effects........................................................................................................ 443 F. Human Clinical Trials ............................................................................................... 443
1. Lethality Extrapolations ..................................................................................... 443 2. Vascular Leak Syndrome ................................................................................... 444
G. Comparison with Abrin Toxicity .............................................................................. 444 VII. Diagnosis and Detection of Ricin Exposure ..................................................................... 445 VIII. Physical Protection ............................................................................................................ 446
A. Field Methods............................................................................................................ 446 B. Inactivation of Ricin.................................................................................................. 446
IX. Treatment and Medical Countermeasures......................................................................... 447 A. Emergency Treatment ............................................................................................... 447 B. Experimental Vaccines.............................................................................................. 447
1. Toxoid Vaccine .................................................................................................. 448 2. Ricin Subunit Vaccines ...................................................................................... 448 3. Neutralizing Epitopes ......................................................................................... 449
C. Experimental Antitoxins............................................................................................ 450 D. Other Experimental Therapeutics.............................................................................. 451
X. Conclusion and Perspective .............................................................................................. 451 Acknowledgments......................................................................................................................... 452 References ..................................................................................................................................... 452
The attractive and deadly Ricinus communis (castor bean plant) has been cultivated for its commercial products, primarily castor seed oil, for at least 4000 years (Olsnes, 2004). Growth of the plant for its oil may have originated in Asia or North Africa, and was likely introduced to the Ancient Greeks and Western civilization through trade with Egypt (Scarpa and Guerci, 1982). Presently, over 1.2 million tons of castor seeds are harvested annually worldwide to produce approximately 220,000 tons of castor oil; the primary producers are India and China (Oil World, 2006). Castor seed contains up to 60% vegetable oil by weight after removal of the spiny seed husk; the oil is highly viscous and very uniform, yielding almost 90% pure, technical grade 12-hydroxy-oleate (ricinoleate) (McKeon et al., 1999). Ricinoleate is a reactive fixed oil that provides the basis for a range of modern products, including dehydrated alkyd resins (used in varnishes, enamels, and paints), biodegradable lubricants (lithium grease), hydraulic fluids, engineering plastics (Polyamide 11), antifungal compounds, cosmetics (lipsticks), soaps, printing inks, plasticizers, wetting agents, and leather dye reagents (Caupin, 1997; McKeon et al., 1999). In addition to castor oil production, the plant serves as a popular ornamental garden bush (temperate regions) or rapidly growing tree (tropical regions).
