While probably originating from Africa, the plant Ricinus communis is found nowadays around the world, grown for industrial use as a source of castor oil production, wildly sprouting in many regions, or used as ornamental plant. As regards its pharmacological utility, a variety of medical purposes of selected parts of the plant, e.g., as a laxative, an anti-infective, or an anti-inflammatory drug, have been described already in the sixteenth century bc in the famous Papyrus Ebers (treasured in the Library of the University of Leipzig). Quite in contrast, on the toxicological side, the native plant has become the “poisonous plant 2018” in Germany. As of today, a number of isolated components of the plant/seeds have been characterized, including, e.g., castor oil, ricin, Ricinus communis agglutinin, ricinin, nudiflorin, and several allergenic compounds. This review mainly focuses on the most toxic protein, ricin D, classified as a type 2 ribosome-inactivating protein (RIP2). Ricin is one of the most potent and lethal substances known. It has been considered as an important bioweapon (categorized as a Category B agent (second-highest priority)) and an attractive agent for bioterroristic activities. On the other hand, ricin presents great potential, e.g., as an anti-cancer agent or in cell-based research, and is even explored in the context of nanoparticle formulations in tumor therapy. This review provides a comprehensive overview of the pharmacology and toxicology-related body of knowledge on ricin. Toxicokinetic/toxicodynamic aspects of ricin poisoning and possibilities for analytical detection and therapeutic use are summarized as well.
The native plant Ricinus communis probably originates from Africa (Ethiopia) or India and is considered as an ancient oil plant of Egypt. Nowadays being distributed worldwide, it is also known under other names, e.g., “Palma Christi” or “wonder tree.” It has a very long and interesting history. The name wonder tree is found in the biblical book Jonah because of the plant’s rapid growth and in the description of the ricinus-feeding worm (Jonah 4; book Jona, chapter 4):
So Jonah went out of the city [Nineveh] ... And the Lord God appointed a castor oil plant [Hebrew: kikayon], and made it to come up over Jonah, that it might be a shade over his head, to deliver him from his distress. And Jonah was exceeding glad of the plant. But God appointed a worm [Hebrew: tola’at] when dawn came up the next day, and it attacked [literally: beat] the plant, so that it withered. And it came to pass, when the sun arose, that God prepared a vehement east wind, and the sun beat down upon the head of Jonah, so that he fainted. (from Hausmann and Müller (2006); see references therein).
The name “Palma Christi” or “Palm of Christ” is based on its ability to heal wounds and cure ailments (Roxas-Duncan and Smith 2012). Indeed, different components of the plant have been described as sanatory ingredients already more than 3500 years ago in the famous Papyrus Ebers which is the only completely preserved papyrus scroll on the ancient Egyptian healing arts in hieratic scripture (Scholl 2002). Interestingly, in Egypt, seeds have been described as ancient means of payment. Already in the 4th millennium bc, ricinus seeds were utilized as grave goods (Germer 1982), indicating their importance for the deceased and the life after death.
The Latin name ricin was first mentioned by the natural scientist Plinius the Elder in the first century in his opus on natural history (NH 15.7.25). It corresponds to the Greek name κροτών, meaning “tick” (Latin: Ixodes ricinus), as well as the ricin tree, and when used in papyri in the plural form, the seeds. According to Plinius, the tree’s name is based on the resemblance of its seeds with ticks. The artepitheton “communis” may indicate its broad distribution (“common”). In the German region, it was first mentioned by Albertus Magnus († 1280 in Cologne), who also cultivated the plant (“arbor mirabilis”). A first botanical description of the plant and its medical characteristics were given by Hieronymus Bock (1498–1554) (von Fischer-Benzon 1894). According to its use as a rich source of plant oil, the plant and the seeds are also named “castor (oil) plant” and “castor bean”, respectively, with the latter also indicating that it resembles a bean (Fabaceae) (Buch 2018 and references therein).
Nowadays, Ricinus communis is found not only in tropical and subtropical regions but also as a wild sprouting or ornamental plant essentially around the world. As a source for castor oil production, the plant is mentioned in connection with different compositions for cosmetic and medical products or within various applications in the industry. Parts of the plant as well as the castor oil itself are among the oldest drugs and have been used in traditional or folk remedies for rituals of sacrifice. Among indigenous peoples (e.g., in Nepal), the use of ricinus seeds has been described as an oral contraceptive (women eat 1–2 beans daily during their fertile days). In alternative medicine, the blow-promoting effect of castor oil is known and explored as so-called blow cocktail in obstetrics. There are also descriptions on its use as a human nutritional supplement, an emetic, or a purgative as well as for treating a wide range of diseases around the world (e.g., Scarpa and Guerci 1982; Poelchen and Wirkner 2003; Olsnes 2004; Rana et al. 2012; Roxas-Duncan and Smith 2012; Tunaru et al. 2012; Abdul et al. 2018; https://www.naturinstitut.info/rizinusoel.html).
On the other hand, the highly toxic component ricin can be isolated from castor beans as well, which is one of the most effective plant toxins (for comparison, see Suppl. Table 1 for examples of representative LD50 values of different kinds of toxins). In fact, for a long time, it has been explored as a possible biological weapon and is still relevant as a bioterrorist agent.
According to Fritz Hauschild, ricin is one of the five most toxic substances known: tetanus toxin, botulinus toxin, diphtheria toxin, gramicidin, and ricin (Hauschild 1960). It may thus not come as a surprise that Ricinus communis has been awarded the title “poisonous plant 2018” in Germany-providing the ideal occasion for a critical appraisal of its relevance (“Giftpflanze des Jahres 2018”; Botanischer Sondergarten Wandsbek: https://www.hamburg.de/wandsbek/giftpflanze-des-jahres).
History-Papyrus Ebers and the plant Ricinus communis
The text from the Papyrus Ebers, the longest and completely preserved papyrus role dealing with the ancient Egyptian art of healing and treasured in the Library of the University of Leipzig, is an informative and unique description dated from the last quarter of the sixteenth century bc. Indeed, it indicates the existence of textual descriptions on the medical use of plants already in the Pharaonic era. The text passages dealing with the ricinus plant (Eb 251, column 47, line 15–column 48, line 3) are often named as “ricinus book” and summarize its curative applications (Fig. 1, column 47, line 15–22). Thus, rather than describing the phenotype of the plant, it focuses on an enumeration of which parts and products of it are useful for treating various maladies. The ancient Egyptian word for ricinus is (in transcription) “dgm”. In contrast to older literature that had identified the plant “k3k3” as ricinus, more recent research, in particular by the Saxonian Academy of Sciences, indicates “dgm” as the correct word, with “k3k3” rather meaning “bushes” in general. Several parts of the plant (radix, seeds, castor oil) have been described in detail for a variety of medical purposes.
Eb 251 (47, 15 - 48, 3): Knowledge of what is made out of the ricinus plant (dgm), as something found in the writings of old, as something useful to man: a) One crushes its roots in water; they are applied to a sick head; he (the patient) gets immediately well like someone who is not ill; b) a little of its fruit is also chewed with beer by one with the whj-symptom, (diarrhoea, Med. Gram. § 299 & G. IX, 72) in his stools; this is an elimination of suffering (b~j·t) in man's belly; c) the growth of woman's hair is also promoted by its seed; it is ground, made into a mass and added to oil (mr/:1:t); then the woman should anoint (gs) her head with it; d) its oil (mr/:1·t) is also prepared from its seed to anoint (gs) (a man) who (has) the w/:1}w-skin disease (and) is affected with i!N (and) bw~w, being unwell. Footnote 1
The credibility of this knowledge is supported by the indication of its existence already in ancient scripts and its long tradition, which has always been a good argument in earlier times. Notably, the amounts to be used are not specified. This must be considered as problematic due to the toxicity of its seeds which may well lead to death (see below).
In total, the Papyrus Ebers describes the following ingredients and indications:
Root + water
Fruit (chewed up) + beer
Fruit (ground) + oil
Oil from the fruit
Exanthema (treatment over 10 days)
Fruit (rushed) + honey
Thus, the Papyrus identifies several parts of the plant as useful. Interestingly, albeit nowadays being primarily used, the oil is mentioned only once in the Papyrus Ebers (for external use in exanthema).
Eb 123 (27, 11 - 27, 14): Another, to eliminate pain-matter: Oil prepared from the ricinus plant (dgm). Who suffers from the wb5·w-skin-dis~ase and is burdened with iU.t (and) Wb5'W from which he is ill, is anointed therewith. The rjwm'w stop as in one whom nothing had befallen. He will also be treated (bnm), however, with ointments (wrb) corresponding to the 10 days during which one anoints (wrb) very early, so that they are eliminated. Really effective, a million times.
The final sentence that it has been proven millions of times provides the additional criterion of quantity. Prescriptions based on plants other than ricinus exist as well, but they often rely on unidentified ingredients. In this regard, ricinus oil is the most straightforward prescription considering ingredients and availability. Also, it seems to be particularly effective in exanthema. Another example, this time related to the head:
Eb 437 (64, 14 - 64, 15): Beginning of the remedies to eliminate the bnsj-t-disease on the head: Fruit of ricinus (dgm) 1; (ox) fat 1; behen-oil 1; made into a mass; bandaged (wrb) with it every day.
The fact that many more prescriptions based on other ingredients derived from other plants, animals, or minerals exist suggests the high prevalence of this disease. A final example explores the use of ricinus as an universal analgesic:
Eb 601 (76, 16 - 76, 18): Another, to eliminate the mr·t-disease in any body-part of man: Ricinus (dgm) fruit; pounded (hb!f); added to honey; dressed therewith.
The anti-inflammatory effect of honey is well known and broadly used (Manjunatha and Chua 2014). It can only be speculated if this effect is enhanced by the crushed ricinus seeds.
Notably, only a very few and clearly identifiable excipients are employed in the context of ricinus: water, beer, honey, fat, oil, and behen oil/olive oil. This has proven to be very helpful since 70–80% of the ingredients and excipients mentioned in the Papyrus Ebers cannot be identified. Often, the ancient Egyptian art of healing uses rather a mix of similia and contraria according to the motto “the more, the better,” since remedies are often composed of dubious ingredients according to the principles “similia similibus curantur” and “contraria contrariis curantur.” It is also interesting to note that religious or magic elements, sometimes found in the Papyrus Ebers, are completely missing in the ricinus prescriptions.
Since the Papyrus Ebers covers remedies, it does not focus on deliberately induced poisoning-despite the widespread fear of poison in ancient times. Thus, only very few prescriptions exist in the Papyrus that are explicitly intended for inducing damage. These are not based on parts of the ricinus plant and are thus beyond the scope of this paper which will rather focus on a description of the plant and its ingredients according to our knowledge nowadays.
The plant Ricinus communis and its most important ingredients
Ricinus communis (Ricinus communis L.) is a member of the spurge family Euphorbiaceae. The plant is the only species and the genus is monotypic (Buch 2018 and references therein). While originating from wet tropics to subtropical dry regions, it grows well in many areas and on different continents around the world (examples are given in Suppl. Fig. 1). In warm regions, it can reach up to 8–10 m in height; it lives for many years and is perennial. The flowers in the upper part of the tip of the spikes are female and bear the fruit (Fig. 2a, b, d). The flowers in the lower part are male and wither after yielding their pollen (Scarpa and Guerci 1982) (Fig. 2a, c, d). At the end of the vegetation period, the green to red-brown seed vessels are developed (Fig. 2e). The fruit is formed by three boxes with separate ripe, with each containing one marmorate seed (Fig. 2f, g). The seeds are oval, bean-like, and light brown, mottled with dark-brown spots and different in length (0.5–2 cm; Bradberry et al. 2003), and have a warty appendage called the “caruncle” (Fig. 2g). The leaves, roots, and seeds are utilized in herbal medicine and beyond. After pressing and extraction of the seeds, the toxin-free castor oil is used in a number of industrial processes and products as well as in medical and cosmetic preparations. Castor bean meal, press cake, and other residues of the castor oil production also serve as a protein source for feed or fertilizer.
From Ricinus communis, various components have been isolated and identified as toxic, for example, the highly toxic ricin (ricin D, RCA60, RCA-II), the less toxic, but highly homologous Ricinus communis agglutinin (RCA120, RCA-I), and the alkaloids ricinine and nudiflorin as well as allergenic compounds (Fig. 3). A number of varieties (cultivars) of Ricinus communis exist. Furthermore, the properties of the constituents in the plant and seeds are influenced by the geographical region, season, period of plant growth, the time point of harvest of the beans, or the moisture content (for review, see Hänsel et al. 1994; Audi et al. 2005; Lopez Nunez et al. 2017). Therefore, a somewhat endogenous variability in the “different cultivars” has been described, also with regard to the protein content (e.g., Despeyroux et al. 2000; Sehgal et al. 2010).
Ricin exists in different isoforms, depending on the seed’s type (size, shape) and plant variety from which it is purified (Despeyroux et al. 2000; Griffiths et al. 2007; Sehgal et al. 2010). Ricin A, B, C, D, and E have been described in the literature (for details, see, e.g. Ishiguro et al. 1971a, b; Lin and Liu 1986; Araki and Funatsu 1987). The name ricin refers to ricin D. Ricin D was purified by gel filtration and cellulose chromatography (Ishiguro et al. 1971a, b). The co-existence of the two highly similar proteins, the cytotoxin ricin D (RCA60) and the hemagglutinin (RCA120), emerged when using improved separation and isolation methods, and by molecular identification of two different genes (Olsnes et al. 1974; Roberts et al. 1985; Lin and Liu 1986).
A number of groups have studied the different ricin isoforms. Sehgal et al. (2010) subfractionated ricin by chromatography into ricin I, II, and III. Molecular weights between 60 and 65 kDa were reported, associated with biological, immunological, and structural differences (Sehgal et al. 2010). Cytotoxicity studies revealed that ricin III is 4–8 times more toxic than the other two forms (Sehgal et al. 2010 and references therein). Leshin and co-workers found that the Ricinus communis genome contains genes encoding seven different but closely related proteins, putative members of the preproricin family of ribosome-inactivating proteins, including ricin toxin and other ricin-like proteins (Leshin et al. 2010).
In 1977, the group of Funatsu isolated a toxic protein distinct from ricin D, referred to as ricin E. Toxicity in mice and cytoagglutinating activity in Sarcoma 180 ascites tumor cells were found equal to those of ricin D, and this cytoagglutination was inhibited by galactose (Mise et al. 1977). In a later paper, ricin E was identified as a fusion product derived from the recombination of the ricin D and Ricinus communis agglutinin genes (Araki and Funatsu 1987). The study of Despeyroux and co-workers revealed a large extent of heterogeneity between different cultivars (the D form which is found in large grain seeds, whereas the small grain seeds seem to contain both D and E forms of ricin toxins) and demonstrated that ricin toxins consist of a series of glycosylated proteins most likely originating from a multigene family (Despeyroux et al. 2000).
Additionally, diverse phytochemicals such as alkaloids, flavonoids, terpenes, saponins, phenolic compounds like kaempferol, gallic acid, rutin, lupeol, ricinoleic acid, pinene, thujone as well as gentisic acid have been described as bioactive compounds in Ricinus communis (see Abdul et al. 2018 and references therein).
(i) The leaves are rich, e.g., in potassium nitrate (Scarpa and Guerci 1982) and ricinine (Waller and Skursky 1972). The separation and determination of the disaccharide glycoside rutin, gentistic acid, quercetin, and gallic acid have been described (Chen et al. 2008). Additionally, the leaves contain a dye that makes a deep blue color (Scarpa and Guerci 1982).
(ii) The castor beans are cultivated for their seeds, yielding the viscous, pale yellow, nonvolatile and nondrying castor oil (Patel et al. 2016). Castor oil becomes even more doughy upon contact with air. A very unpleasant taste has often been described as scratching the throat.
The castor oil seeds contain about 45–55% oil and up to 25% protein as well as carbohydrates (e.g., fructose, glucose, saccharose), squalen, succinic acid, bitter compounds, lecithin, and others (Hänsel et al. 1994; Frohne and Pfänder 2004). Other references also report castor oil to contain up to 90% ricinoleic, 4% linoleic, 3% oleic, 1% stearic, and less than 1% linolenic fatty acids (Patel et al. 2016 and references therein).
(iii) The oily cake of pressed seeds, generated in large quantities from the process of castor oil production, contains ~ 3% ricin (Weber 2014) and ricinin as well as allergenic compounds (e.g., castor bean allergenic fraction CB-1A). After oil extraction and detoxification, the defatted press cake is used as low-value feed and as organic fertilizer, e.g., because of its high nitrogen content or the fast rate of mineralization (see Worbs et al. 2011; Severino et al. 2012 and references therein).
The evaluation of extracts of Ricinus communis also identified insecticidal properties, e.g., against aphids (Olaifa et al. 1991), tobacco mosaic virus infection (Taylor et al. 1994), Anopheles arabiensis or Culex quinquefasciatus (Elimam et al. 2009; Wachira et al. 2014), and a number of other activities (see, e.g., Upasani et al. 2003; Zahir et al. 2010; Abdul et al. 2018). Furthermore, the anti-nematode effect of castor meal was found (Severino et al. 2012 and references therein).
Finally, Ricinus communis shows an interesting affinity towards heavy metals. For example, it has been described as a hyperaccumulator of lead and an effective accumulator of nickel and, to a lesser extent, of cadmium (for references, see Severino et al. 2012). The growth was inhibited when, e.g., cadmium, lead, copper, nickel, and zinc were added to the soils.
Cold-pressed oleum ricini can contain up to 90% of ricinoleic acid, as triglyceride of the hydroxylated unsaturated fatty acid (IUPAC, (9Z,12R)-12-hydroxyoctadec-9-enoic acid). Castor oil has been used as a purgative and is described as an effective laxative. After oral intake of the castor oil, the triglyceride is hydrolyzed by intestinal lipases into glycerol and ricinoleic acid. It exerts a laxative effect by irritating the intestinal mucosa and induces labor in pregnant females (Teuscher and Lindequist 2010; Tunaru et al. 2012). In addition to effects on intestinal ion transport and water flux, ricinoleic acid can directly influence intestinal motility. Tunaru and co-workers could show that ricinoleic acid specifically activates the prostanoid receptor (EP3) for prostaglandin E2, suggesting a possible role of the EP3 receptor as a target in the induction of laxative effects (Tunaru et al. 2012 and references therein; see Castor oil for more details).
Furthermore, in several models of acute and subchronic inflammation, ricinoleic acid has been shown to exert analgesic and anti-inflammatory effects after topical application (Vieira et al. 2000). Interestingly, pharmacological analyses demonstrated similarities between the effects of ricinoleic acid and those of capsaicin, suggesting a potential interaction of the ricinoleic acid on sensory neuropeptide-mediated neurogenic inflammation. Anti-inflammatory and analgesic properties of some ricinoleic acid derivatives are also highlighted (Pabis and Kula 2016). Finally, ricinoleic acid also acts as a specific algicide for the control of cyanobacteria (formerly called blue-green algae) (US 4398937, 1983).
Ricin (ricin D, RCA-II, RCA60)
Ricin D is stored in vacuoles within the endosperm cells of mature ricinus seeds and is prone to rapid degradation by hydrolysis during the early stages of post-germination growth (see Hänsel et al. 1994; Hartley and Lord 2004; Greenwood et al. 2005; Lord and Spooner 2011; Tyagi et al. 2015; Lopez Nunez et al. 2017 and references therein). While the endogenous function of ricin within the plant remains elusive, it is speculated that its profound cytotoxicity might serve as a defense against all sorts of herbivorous or other plant-damaging organisms (Worbs et al. 2011 and references therein).
The seminal work of R. Kobert and co-workers (University of Dorpat; now University of Tartu, Estonia) on plant toxalbumins has elucidated the toxic principle of Ricinus communis. His assistant H. Stillmark described a toxin that caused agglutination of erythrocytes and precipitation of serum proteins and termed it ricin (Stillmark 1888; Kobert 1906).
Nowadays, ricin is classified as a type 2 ribosome-inactivating protein (RIP2) and is characterized as a disulfide-linked heterodimer (AB toxin) of ~ 62 kDa, comprising a covalently linked A (~ 32 kDa) and B subunit (~ 34 kDa) (Funatsu and Funatsu 1977; Lord et al. 1994). The catalytically active A subunit (A chain; RTA) irreversibly inactivates ribosomes, leading to irreversible inhibition of protein synthesis and eventually resulting in cell death.
The comparison of the protein sequence of RTA with type 1 RIPs revealed generally low identities (Suppl. Fig. 2; Fabbrini et al. 2017). Higher protein sequence identities and homologies are found when comparing ricin and mistletoe lectin (ML-I) from Viscum album (Suppl. Fig. 3).
Degenerative alterations were observed following ricin application to feline dental pulps (Henry et al. 1987). The injection of ricin into the rat facial nerve resulted in “suicide transport” and rapid degeneration of facial motor neurons (Streit and Kreutzberg 1988). Ricin is transported retrogradely by the axons to the cell bodies, causing selective destruction of the neurons in the ipsilateral nodose ganglion as well as those in the dorsal motor nucleus (see Ling et al. 1991 and references therein). Sequential degenerative changes of the sensory neurons as well as the accompanying response of the satellite cells were described (Ling et al. 1991). Törnquist and co-worker investigated the response of glial cells and the activation of complement following motor neuron degeneration upon ricin injection into the hypoglossal nerve (Törnquist et al. 1997). Ricin, when injected into skeletal muscles or peripheral nerves, mimics the syndrome of human motor neuron disease since it affects only motor neurons and sensory neurons (de la Cruz et al. 1994). Ricin is also effective in the inhibition of the protein synthesis in vitro in cell cultures enriched for microglial cells, astrocytes, or cerebellar granule neurons. The glial cells, in particular microglia, are very sensitive to RIP toxicity (ricin, volkensin) and are hypothesized to be a primary target of these toxins when injected in vivo (Sparapani et al. 1997).
Ricinus communis agglutinin (RCA120)
Beyond ricin, the seeds also contain Ricinus communis agglutinin (RCA120; ~ 120 kDa, comprising two A (~ 32 kDa) and B subunits (~ 36 kDa)), respectively. The homology between RCA120 and ricin (RCA60) is over 93% between the A chains and 84% between the B chains (Roberts et al. 1985). Amino-terminal sequencing of ricin and RCA120 has shown that the A subunits are identical up to residue 7 and the B subunits are homologous at least in the first 19 residues (see Butterworth and Lord (1983) and references therein). Albeit being highly homologous to ricin, it is categorized as a protein with considerable lower toxicity. Unlike ricin, RCA120 is not directly cytotoxic but shows affinity for red blood cells, leading to agglutination and subsequent hemolysis (see Audi et al. 2005; Severino et al. 2012 and references therein). Ricinus communis agglutinin is not significantly absorbed from the gut, thus causing clinically significant hemolysis only after intravenous administration (Balint 1974; Audi et al. 2005).
Ricinine (IUPAC: 4-methoxy-1-methyl-2-oxo-1,2-dihydropyridin-3-carbonitrile) is an alkaloidal toxin (molecular weight = 164.2 g/mol), belonging to the group of piperidine alkaloids. It is found in small amounts in all parts of the plant, including the leaves and the pericarp (e.g., the seeds contain approximately 0.2% of the alkaloid) and translocates in the plant depending on the age (Waller and Skursky 1972; see Audi et al. 2005; Worbs et al. 2011 and references therein). LD50 values for ricinine (mice) were determined at 3 g/kg upon oral incorporation and 340 mg/kg upon intraperitoneal application (Ferraz et al. 1999).
Ricinine is stable in human urine when heated up to 90 °C for 1 h as well as upon storage at 25 °C, 5 °C, or − 20 °C for 3 weeks (Johnson et al. 2005). Furthermore, unlike ricin, ricinine cannot be inactivated by conventional heat treatment due to its high temperature resistance (melting point ~ 200 °C) (Worbs et al. 2011). Since ricinine can be coextracted with ricin, it can be used as a surrogate marker for tracking intoxications caused by crude plant extracts (Darby et al. 2001; Lopez Nunez et al. 2017; Robert Koch Institut 2017).
In animal models, Ricinus communis extracts exert typical CNS-stimulating and neuroleptic effects, whereas ricinine has been described to elicit hyperreactivity, clonic seizures accompanied by electroencephalographic alterations, and subsequent death (Ferraz et al. 1999, 2002). Data of Ferrenz and co-workers suggest that an increased release of glutamate in the cerebral cortex can be implicated in the genesis of ricinine-induced seizures and that it triggers many anticonvulsive mechanisms, like the release of Tau, dopamine, serotonin, and noradrenaline (Ferraz et al. 2002).
The powdered leaves of the plant have been used for repelling aphids, mosquitoes, white flies, and rust mites, probably due to the presence of the alkaloid ricinine (Olaifa et al. 1991; Rana et al. 2012). In fact, the alkaloid was described to act as a repellant or a toxin against insects, e.g., the leaf-cutting ant (Atta sexdens rubropilosa) or a noctuid moth (Spodoptera frugiperda) and has therefore attracted interest with regard to crop protection (Bigi et al. 2004; Cazal et al. 2009; Lopez et al. 2010).
Pollen and seed components of Ricinus communis can exhibit an allergenic potential, associated with urticaria as well as conjunctivitis or rhinitis (Bradberry et al. 2003; Teuscher and Lindequist 2010; Deus-de-Oliveira et al. 2011; Severino et al. 2012). Beyond laboratory personnel, castor bean allergies have been found in various industrial sectors, namely in workers employed in fertilizer retail, in the upholstery industry, or in oil-processing mills (Deus-de-Oliveira et al. 2011). Regarding the latter, endemic asthma caused by castor bean dust has been observed in the proximity of a castor oil mill, and workers occupationally exposed to castor bean dust exhibited the allergic syndrome (see Bradberry et al. 2003; Severino et al. 2012; Patel et al. 2016 and references therein).
Both type I and IV allergenic responses have been described following dermal exposure to castor bean dust, as well as the involvement of eosinophils and IgE receptors (Bradberry et al. 2003 and references therein). Spies and Coulson isolated a protein fraction and called it CB-1A (Spies and Coulson 1964). CB-1A belongs to a family of low molecular weight storage proteins named 2S albumins that is present in seeds of a wide range of dicotyledonous plants (for references, see Severino et al. 2012). Specific IgE antibodies against the 2S storage albumins have been detected in most (96%) castor-sensitive patients (Thorpe et al. 1988; Deus-de-Oliveira et al. 2011). Other isoforms of allergenic 2S albumins were determined and named Ric c 1 and Ric c 3, and critical amino acids in the IgE-binding epitopes in these isoforms have been identified (Deus-de-Oliveira et al. 2011; Severino et al. 2012 and references therein). It has been suggested that these castor allergens Ric c 1 and Ric c 3 are a new class of amylase inhibitors and may play a role in plant defense, based on their inhibition of insect α-amylase (Nascimento et al. 2011).
The castor bean exhibits powerful lipase activity, which is responsible for the hydrolysis of triglycerides (Srivastava et al. 2016). Lipase activity is localized in the spherosomes derived from endosperm tissue of the seeds and, in contrast to other oilseeds, the castor bean lipase is activated in dormant seeds and in germinated seeds (Ory et al. 1968; Srivastava et al. 2016). More specifically, two lipases have been described in extracts from castor bean endosperm, one with optimal activity at pH 5.0 (acid lipase; associated with the membranes of spherosomes) and the second with an alkaline pH optimum (alkaline lipase; associated with the membrane of glyoxysomes and the endoplasmic reticulum) (Muto and Beevers 1974; Eastmond 2004; Srivastava et al. 2016). Furthermore, Morlon-Guyot and co-worker have shown that ricin possesses a functional lipase active site at the interface between the two subunits. The structural examination of type II (synonymous to “type 2” as found in other references) RIPs indicated that this lipase site is present in toxic (ricin, abrin) members of this family, but that it is altered in lesser toxic or nontoxic (mistletoe lectin I, ebulin 1) members (Morlon-Guyot et al. 2003). This finding further indicates that lipolytic activity likely plays an important role in RIP cytotoxicity.
Nowadays, ricinus lipase derived from press cake is employed in industrial fat processing. Notably, lipases represent one of the most abundantly described groups of enzymes in the context of biofuel production. More specifically, it is used for the processing of glycerides and fatty acids for biodiesel (fatty acid alkyl esters) production (Ribeiro et al. 2011).
Mechanisms of ricin action
As described above, ricin is a heterodimer (AB toxin) consisting of a sugar-binding B chain (~ 34 kDa; 262 aa) linked via a single disulfide bond to the catalytically active A chain (~ 32 kDa; 267 aa). This results in a holotoxin of about 65 kDa (Lappi et al. 1978; Lord and Spooner 2011; Worbs et al. 2011 and references therein). The mechanism of action and toxic principle of ricin have been studied among others by Endo and co-workers, characterizing ricin (and other plant toxalbumins) as RNA N-glycosidases (Endo and Tsurugi 1987; Endo et al. 1987). Notably, ricin-related toxins like abrin and modeccin exert similar activities on 28S rRNA, suggesting a more general mechanistic pathway for ribosome inactivation by lectin toxins (Endo et al. 1987).
Ricin preferentially binds through the catalytically inactive B chain, a lectin with galactose- and N-acetylgalactosamine specificity, to carbohydrate residues on the cell surface, thus facilitating the internalization of ricin into the cytosol (for a schematic illustration, see Fig. 4). In fact, several oligosaccharide residues including N-acetylglucosamine and galactose residues on glycolipids and glycoproteins, which are broadly present on mammalian cells, have been identified as receptors for the lectin subunit (Worbs et al. 2011). Additionally, a mannose receptor (MR; CD206)-mediated uptake of the ricin toxin has been described (Simmons et al. 1986; Magnusson et al. 1993; Gage et al. 2011).
Ricin is internalized through clathrin-dependent and clathrin-independent endocytosis. It undergoes retrograde transport from endosomes to the Golgi apparatus towards the endoplasmic reticulum (ER). In the ER, a disulfide isomerase mediates the cleavage of the disulfide bond between the A and B chain, allowing the cytotoxic A chain to translocate across the membrane of the ER into the cytosol (Lappi et al. 1978; Lord and Spooner 2011; Sandvig et al. 2013; Tyagi et al. 2015 and references therein). Here, through removal of a single adenine residue from the so-called sarcin loop of the eukaryotic 28S rRNA (position 4324; leading to depurination), the A chain irreversibly inactivates eukaryotic ribosomes and thus inhibits protein synthesis (Lord et al. 1994; Hartley and Lord 2004; Tyagi et al. 2015). On the mechanistic side, this involves the hydrolytic cleavage of the N-glycosidic bond of A4324 of the 28S rRNA (Endo et al. 1987; Endo and Tsurugi 1987). This adenine, however, is the binding site for elongation factors 1 and 2, and the depurination profoundly impairs the ribosomal elongation cycle, rendering these ribosomes incapable of binding translation factors and thus abolishing protein synthesis. This results in cell death, thus accounting for the extreme cytotoxicity of ricin (for review, see Lord and Spooner 2011). Functional domains like the α-helix formed by residues 99–106 have been identified as instrumental in the control of ricin’s depurination activity (Dai et al. 2011). Finally, Taubenschmidt et al. discussed a potential interplay between fucosylation, galactosylation, and sialylation with regard to ricin toxicity, since they identified for the first time an extremely high specificity of ricin for defined glycosidic structures that determine the cellular fate upon ricin exposure (Taubenschmid et al. 2017).
Apart from protein synthesis inhibition, other cytotoxic mechanisms have been put forward (examples of important cellular studies on ricin are listed in Table 1 and examples of the important toxic effects of ricin are shown in Suppl. Fig. 4). These include electrolyte imbalance, damage to cell membranes or alterations in their structure and function, the release of cytokines as mediators of inflammation, hepatic oxidative stress, and the direct induction of apoptosis (Audi et al. 2005; Worbs et al. 2011; Tyagi et al. 2015; Lopez Nunez et al. 2017). Consequently, in animal studies elevated plasma ALT and AST levels were found upon administration of ricin A chain, indicating hepatotoxicity and increasing inflammatory responses (Buonocore et al. 2011). Finally, it has also been shown that seeds, stem, leaves and root methanolic extracts from Ricinus communis induced mild to moderate cytotoxicity against human or bovine red blood cells and also exerted mild mutagenicity (Abbas et al. 2018).
Strikingly, only a single ricin A-chain molecule is sufficient for inactivating >1500 ribosomes per minute, and thus to induce cell death (Audi et al. 2005). A number of studies aimed at influencing these mechanisms for the specific manipulation of the ricin activity (see below). Among others, this has led to the identification of a “druggable” sugar code that is evolutionary conserved and can be manipulated for controlling toxicity of ricin (Taubenschmid et al. 2017).
Ricin is one of the most toxic plant toxins. The ricin content can be up to 1–5% (w/w) of the beans of the castor oil plant (Balint 1974; Bradberry et al. 2003). Precision and reproducibility of its toxicity are influenced by a considerable number of factors:
(i) As described above, ricin dosages and toxic effects estimated from the number of beans ingested may be inaccurate due to the plant varieties and variations in region-dependent growth conditions as well as the quality of the beans.
(ii) The features and severity of ricin toxicity/poisoning vary markedly with the dosage and route of exposure/uptake (oral, inhalative, per injection, dermal) and furthermore, on the individual’s side, from the degree of mastication, age, and comorbidities (for review, see Bradberry et al. 2003; Audi et al. 2005).
(iii) When characterizing ricin toxicity (kinetics, esp. distribution and excretion) in the lab, results also depend on the experimental system used, e.g., cell culture conditions and assays in vitro, animal species, strains, age, sex, and feeding conditions used in vivo as well as the injection/intake route and observation time (e.g., Roy et al. 2012).
Thus, extrapolating results from animal experiments towards humans remains difficult. Still, the following numbers are often cited (see also Table 2): (i) The lethal dose by inhalation (breathing in solid or liquid particles) and injection (into muscle or vein) has been estimated to be approximately 5–10 μg/kg body weight in man, i.e., 350–700 μg for a 70-kg adult (Bradberry et al. 2003). (ii) When analyzing cases of poisoning upon castor bean ingestion, the lethal oral dose for ricin in humans has been estimated at ~ 1–20 mg ricin/kg body weight (equivalent to approximately 8 beans, Audi et al. 2005). In reports documenting clinical symptoms (mild to lethal), the number of beans ingested range from 0.5–30 (Challoner and McCarron 1990; Audi et al. 2005; Worbs et al. 2011). Concomitantly, while it has been reported that up to 1 mg pure toxin can be isolated from 1 g seeds, representing a lethal dosage, other references rather describe 1–6 or 10–20 seeds to be toxic in children or adults, respectively (see Roth et al. 2008; Thiermann et al. 2013 and references therein).
For comparison, the LD50 values in mice are ~ 3–24 μg/kg after injection or inhalation and ~ 20–30 mg/kg after castor seed ingestion-which is approximately 1000-fold higher (see also Table 3; e.g., Franz and Jaax 1997; He et al. 2010; Audi et al. 2005, Worbs et al. 2011 and references therein). A number of case reports on intoxication have been published, including the prominent umbrella attack on the Bulgarian dissident Georgi Markov (killed in 1978 with the tip of an umbrella while waiting for a bus in a London street; Crompton and Gall 1980). Very comprehensive summaries of ricin intoxications in humans due to castor seed ingestion are given by Worbs et al. (2011) and Roxas-Duncan and Smith (2012).
Ricin is available, e.g., as crude impure plant extract, purified crystals, powder, and solution. Purified ricin is a white powder that is soluble in water and stable under ambient conditions. Heating for 10 min at 80 °C or for 1 h at 50 °C (pH 7.8) may lead to its inactivation (Burrows and Renner 1999; Audi et al. 2005; Vitetta et al. 2006).
The effects of ricin (clinical symptoms) are directly related to the route of administration: oral, parenteral, inhalative, or dermal. Furthermore, different individual factors of the patients are also responsible for the progress and the symptomatology (Robert Koch Institut 2017).
The therapy of ricin intoxication is symptomatically. The standard procedure is a rapid primary elimination of the toxin (asservation and control of the stomach contents). The prompt treatment with supportive care is necessary to limit morbidity and mortality. It is important to note that in pre-clinical studies the passive immunization with anti-ricin neutralizing antibodies has been identified so far as the only post-exposure measure effective against pulmonary ricinosis at clinically relevant time points following intoxication (Gal et al. 2017). The efficacy of this anti-toxin treatment depends on the antibody affinity and the time of treatment initiation within a limited therapeutic time window.
An overview of the four ways of intoxication and some characteristics is given in Table 4 and briefly discussed in the following.
(i) Routes of intake: Food and water contamination; castor beans found in jewelry (necklaces and bracelets); unintended uptake by children due to the bean’s resemblance to nuts, i.e., children were observed eating castor beans because of their attractive, hazelnut-like appearance and the typical taste of the seeds.
(ii) Further remarks: Ricin toxin is not released from the bean until it has been chewed and digested, thus allowing ricin from the formerly intact seed capsule with little toxicity into the gastro-intestinal tract. Intoxication depends on the degree of the crushing and from the stomach contents (Roy et al. 2012; Robert Koch Institut 2017). After oral ingestion, ricin is stable towards gastrointestinal proteases and is absorbed from the gastrointestinal tract (Bradberry et al. 2003; Balint 1974). Release of toxin from beans is generally in the ileum or colon (Roy et al. 2012).
(i) Routes of intake: Stab wounds, injection (i.m. or s.c., among others), incisions. After application, the toxin is systemically distributed in the body, followed by a severe disease process and impairment of body functions (Robert Koch Institut 2017).
(ii) Further remarks: Ramsden and co-workers studied the distribution and excretion of ricin in rats after intravenous injection of [125I]-labeled ricin (equal in toxicity to native ricin) (Ramsden et al. 1989). After 30 min, they identified the liver as the major organ of localisation (46% of injected dose), with the spleen and muscle being next (9.9% and 13%, respectively) while levels in lymph nodes were found very low (1.2% / g). Ricin was quickly cleared from the animal; only 11% of the initial radioactivity was left after 24 h, while 70% was excreted in the urine (Ramsden et al. 1989).
(i) Routes of intake: Ricin poisoning by inhalation as aerosol (ricin powder/ricin dusts; ricin solutions, grist (fertilizer)), as observed in the proximity of ricin mills. Ricin dusts were found to induce immunological reactions in exposed individuals, e.g., in the periphery of factories producing castor oil.
(ii) Further remarks: The toxic effect of ricin after inhalation (aerosol) depends on various factors including the humidity at the time point of exposure, injuries of the lung, and particle sizes of the aerosol, determining the penetration depth into the lung (Audi et al. 2005; Griffiths 2011; Roy et al. 2012). Particles of low micron size were found to deposit deeper in the respiratory tract, resulting in higher mortality (Griffiths et al. 1995; Audi et al. 2005). In contrast, larger particles typically deposit higher in the airways, and can thus be swept out by the mucociliary system and subsequently swallowed (Roy et al. 2012).
(i) Routes of intake: Skin exposure of ricin meal/grist used as fertilizer or in the area of ricin mills leads to allergic reactions. Intoxication is also possible through the conjunctiva.
(ii) Further remarks: Biochemical studies have demonstrated lipophilic properties of ricin, leading to dermal absorption. However, no systemic distribution was found, indicating that this intoxication route as less relevant. In fact, in the case of intact skin, no examples for systemic intoxication have been described beyond the strong sensibilization potential, while after skin injuries local dermal intoxication can be observed.
From past to present-pharmacological and technical use
Beyond castor oil, a number of its phytochemical ingredients have been studied for their pharmacological and therapeutic effects. These include anti-microbial, anti-fungal, anti-cancer, anti-diabetic, anti-inflammatory, anti-malaria, anti-oxidant, central analgesic, anti-convulsant, anti-nociceptive, anthelminthic, anti-fertility, laxative, uterine contracting, anti-implantation, anti-asthmatic, bone regenerative, molluscicidal, anti-ulcer, anti-histaminic, wound-healing, insecticidal, anti-arthritic, anti-dandruff, and hepatoprotective activities (see Hänsel et al. 1994; Abdul et al. 2018). Furthermore, a novel fusion protein between ricin A chain (RTA) and pokeweed anti-viral proteins (PAPs; Phytolacca Americana) has been developed. This “RTA-PAPS1” possesses significantly increased inhibitory effects on protein synthesis and anti-hepatitis B virus (anti-HBV) activity in vitro and merits further development as a potentially potent anti-viral agent for the treatment of chronic HBV infection (Hassan et al. 2018).
Castor oil-technical use
Castor oil has long been used in different ways, e.g., as an inexpensive fuel for oil lamps as already described in the Papyrus Ebers. Nowadays, castor oil production is the most important use of the ricinus plant. The castor seeds contain 40–50% oil. Between 2009 and 2013, the average annual world production of castor oil seed was approximately 1.99 × 106 tons (Mensah et al. 2018) and represents ~ 0.15% of the total vegetable oil produced worldwide (Severino et al. 2012).
Cold or hot pressing of the beans, followed by solvent extraction, allowed for the production of different kinds of oils and lubricants. Castor oil offers a number of advantages, making it an important feedstock utilized by industry (see Suppl. Fig. 5). These include, for example, the high proportion of the fatty acid ricinoleic acid as well as the presence of a number of functional groups useful for performing a variety of chemical reactions (including halogenation, dehydration, alkoxylation, esterification, sulfation; Ogunniyi 2006; Patel et al. 2016; Mensah et al. 2018). For a more detailed description and critical appraisal of the potential of castor oil in the context of biotechnology and industrial uses, including renewable fuels, the reader is referred to the literature (e.g., Mutlu and Meier 2010; Severino et al. 2012; Mensah et al. 2018).
The processed or refined castor oil is devoid of all toxic proteins and can thus be safely used for pharmacological and pharmaceutical applications (in particular, the toxic ricin is insoluble in oil and any residual ricin is thus eliminated during the refining process). In conventional, alternative, and folk medicine, castor oil is still in use as a stimulant laxative. It is generally recognized and classified as safe by the Food and Drug Administration (FDA). The Joint Food and Agriculture Organization (FAO)/World Health Organization (WHO) Expert Committee on Food Additives established an acceptable daily castor oil intake (in humans) of up to 0.7 mg/kg body weight (Final report on the safety assessment of Ricinus communis (Castor) Seed Oil (2007)). Yet, the clinical use of castor oil as a laxative has been decreasing in conventional medicine, while it is still used widely in alternative and folk medicine (Tunaru et al. 2012; Patel et al. 2016 and references therein). However, due to its very strong effects possibly leading to abdominal cramps and its unpleasant taste, it is nowadays considered as obsolete.
On the mechanistic side, the laxative effects of ricin oil were found to be based on their triacylglyeroles of ricinoleic acid contents. While the triglyceride is inactive, it is hydrolyzed by lipases in the small intestine, releasing ricinoleic acid. By triggering the release of prostaglandin E2, it leads to enhanced intestinal motor activity, inhibition of water resorption, and thus increased water and electrolyte secretion into the gut. Tunaru and co-workers reported on the mechanism by which castor oil exerts its effects on gut and uterus motility, inducing laxation and uterus contraction (see also part Ricinoleic acid). They could show that ricinoleic acid is a selective agonist of prostaglandin E receptors (EP3 and EP4), mediating the pharmacological effects by activation of EP3 receptors on smooth-muscle cells. The authors verified that EP3 and EP4 receptors are expressed in MEG-01 cells and that prostaglandin E2 has effects comparable to ricinoleic acid (Tunaru et al. 2012). These results also suggested EP3 receptors as potential targets for drugs to induce laxation. For research purposes, castor oil has also been administered orally to induce diarrhea in rats. This has led to the establishment of a bioassay for the measurement of anti-diarrhea activity, representing a fast and efficient method for preliminary screening for potential drug-like candidates from natural products (for references, see Patel et al. 2016).
Finally, castor oil and hydrogenated castor oil are used as ingredients in cosmetics, e.g., in lipsticks or hair care products; as supplement in deodorants (zinc ricinoleate), hand creams, and lotions; or in products for foot care. Refined ricinus oil is employed for the purpose of injections and in eyedrops (Final report on the safety assessment of Ricinus communis (Castor) Seed Oil (2007); Arnold 2017).
In modern medicine, castor oil or derivatives like Kolliphor EL (polyethoxylated castor oil, a nonionic surfactant) are also used as a drug delivery vehicle, e.g., for very nonpolar drugs such as the anti-cancer drugs paclitaxel and docetaxel (for references, see Patel et al. 2016). Furthermore, castor oil has been used as a solvent, co-solvent, stabilizing agent, and polyol for the formation of polymer-nanoparticle composites. It provides a facile route of nanoparticle surface functionalization and nanoparticle coating with polymers (Mensah et al. 2018).
Ricin as immunoconjugate/immune toxin in tumor therapy
Ricin has great therapeutic potential, for example, as an anti-cancer agent, in bone marrow transplantation, or in cell-based research, and is even explored in the context of nanoparticle formulations in tumor therapy.
The cytotoxic effects of ricin on tumor cells were already observed in the early 1950s, and thus well before the description of ricin’s molecular structure and mode of action (Mosinger 1951). Initial findings in sarcomas in rat were further extended by Lin and co-worker who described prolonged survival of mice bearing Ehrlich ascites tumors upon ricin treatment (Lin et al. 1973), and in a human xenograft mouse model (Fodstad and Olsnes 1977). The observed higher sensitivity of cancer cells towards ricin may be attributed to their higher proliferation rate, requiring a higher rate of protein synthesis and thus making them more prone to ricin-mediated inhibition of this process, and/or to a higher ricin (B chain)-receptor concentration on the surface of tumor cells, allowing for enhanced uptake. An initial phase I study in 54 cancer patients with advanced disease indicated some therapeutic effects in a few patients (Fodstad et al. 1984). Still, however, this binding specificity was found insufficient, with ricin binding to virtually every cell type (Audi et al. 2005). Consequently, this led to the development of immunotoxins instead. In this approach, the biologically active component (here: ricin A chain) is covalently coupled to an antibody or other ligand that serves as binding moiety for selectively binding to the target cells (here: tumor cells). While initial ricin A-chain immunotoxins were found highly selective towards their target cells, their efficacy was poor (Neville Jr and Youle 1982; Wawrzynczak et al. 1991). This discrepancy was attributed to the mechanism of uptake and intracellular trafficking, with its processing in the endosomal/lysosomal system leading to rapid degradation, thus preventing the ricin A chain to reach the cytoplasm and thus its site of action (Preijers et al. 1988; van Horssen et al. 1995). In contrast, higher activity was achieved upon routing of immunotoxins through the Golgi complex (Press et al. 1986). A shift towards trafficking through the Golgi complex also provided the explanation for the finding of enhanced toxicity of a ricin A-chain immunotoxin upon addition of free ricin B chain (Neville Jr and Youle 1982; Timar et al. 1991). In addition to its binding properties, the ricin B chain was also found to have a role in the translocation of the membrane-bound A chain to the cytoplasm and in its intracellular routing (Timar et al. 1991), and to exert some pro-apoptotic effects by itself (Hasegawa et al. 2000). Consequently, immunotoxins based on the conjugation of the whole ricin molecule, rather than its A chain alone, were found to be more efficient (Olsnes 2004 and references therein). In this context, it should also be noted that, beyond its inhibitory effect on protein synthesis, other modes of action have been described. These include the release of pro-inflammatory cytokines, lipid bilayer destabilization, and the direct induction of apoptosis (Griffiths et al. 1987; Hughes et al. 1996; see also Suppl. Fig. 4). The latter is mainly, but perhaps not exclusively, triggered by the intrinsic pathway (activation of caspases 9 and 3), increased ROS (reactive oxygen species) production, and DNA fragmentation/impaired DNA repair (Komatsu et al. 1998; Kumar et al. 2003; Wu et al. 2004; Rao et al. 2005), leading to various downstream effects (Slominska-Wojewodlzka and Sandvig 2013 and references therein).
Initially, the ricin A chain, devoid of its B chain, was directly coupled to antibodies. This approach, however, could not prevent non-specific binding and uptake of the A chain (even without its B-chain-based binding properties) to various cells including macrophages and Kupffer cells (Fulton et al. 1988). This was mediated by carbohydrate residues on the A chain serving as binding partners for mannose receptors on the liver cells (Bourrie et al. 1986). Consequently, side effects were reduced and lifetimes in mice were prolonged by chemical deglycosylation of the A chain (Blakey et al. 1987; Fulton et al. 1988). Beyond the above-mentioned roles of the B chain leading to enhanced A-chain cytotoxicity, a protective role against cathepsin-mediated proteolysis of the A chain was described as well (Bilge et al. 1994). Further improvement was achieved by generating an altered ricin, the so-called blocked ricin, based on chemically blocking two galactose-binding sites of ricin by its chemical modification with affinity ligands (Lambert et al. 1991). Despite substantially reduced binding activity and cytotoxicity of blocked ricin, the catalytic activity of the A chain and the translocation role of the B chain were retained (Lambert et al. 1991).
Over the last decades, considerable work has been published on immunotoxins and other toxin conjugates. This also includes ricin, and various preclinical and clinical studies have been conducted (see Table 5 and Slominska-Wojewodlzka and Sandvig 2013; Tyagi et al. 2015).
Major side effects associated with ricin-based immunotoxins are its low blood circulation time, immunogenicity, non-specific binding, and, as main side effect of ricin-derived immunotoxins, the vascular lead syndrome (VLS). Ribosome-inactivating proteins are often associated with high immunogenicity, thus limiting efficacy of treatment and the time period until an antibody response is detected, possibly leading to severe side effects. VLS, induced by ricin reaching the capillary endothelial cells, is a common dose-limiting toxicity and is associated with tissue edema and multi-organ failure (Baluna et al. 1999). It involves vascular endothelial cell damage, extravasation of fluids and proteins into tissues, interstitial edema, and organ failure (Baluna and Vitetta 1997). Despite detailed knowledge on the mechanism, it is believed to be mediated by the A chain rather than the cell-binding B chain.
Ricin in nanoparticle formations
In the light of unwanted side effects associated with the potential use of ricin in tumor therapy, several studies have looked into various nanoparticle formulations of ricin or the ricin A chain. In general, nanoparticles for the transport of drugs are explored with regard to altering biodistribution towards preferential delivery into on-target organs over off-target organs, enhanced blood circulation time/reduced degradation and elimination, increased penetration through biological and physiological barriers, enhanced efficacy of cellular uptake, and improved intracellular trafficking, for example, with regard to endosomal release. When decorating nanoparticles with specific ligands, efficient and selective targeting of the cells of interest is feasible as well. Altogether, these properties aim at leading to improved bioavailability and/or reduced side effects in non-target organs/cells. Lipid-based nanoparticles are the most advanced carriers, and have been extensively explored for ricin delivery. Inorganic nanoparticles may offer advantages with regard to stability and non-sensitivity against enzymatic or microbial degradation, but this non-biodegradability can also be an issue. Polymeric systems have gained increasing importance for example in the field of oligonucleotide delivery, and allow for numerous possibilities for structure modifications and custom-designable properties.
In oncology, nanoparticle delivery can benefit from the so-called passive tumor targeting due to the enhanced permeability and retention (EPR) effect, based on blood vessels presenting large fenestrations and gaps, distinct vessel irregularities, increased permeability, and lack of a normal lymph drainage as a consequence of increased angiogenesis and hypervascularization (Jang et al. 2003; Pecot et al. 2011). Thus, after transfer through endothelial fenestrations (permeability) facilitated by their nanosize, nanoparticles show a tendency to accumulate in the tumor tissue and are retained in the irregularly structured tissue (retention). Beyond this, active targeting explores the selective accumulation of nanoparticles on the surface of cancer cells, based on the binding of selective ligands presented on the nanoparticle surface.
As early as in the late 1970s, the encapsulation of ricin into negatively charged liposomes was described, leading to enhanced cytotoxicity or the circumvention of cellular ricin resistance (Nicolson and Poste 1978; Dimitriadis and Butters 1979). The latter was also true upon entrapping ricin into unilamellar liposomes (Gardas and Macpherson 1979). A considerable number of studies showed that monesin, a carboxylic ionophore and lysosomotropic agent, was able to potentiate the activity of ricin or ricin-based immunotoxins. This was true for monesin encapsulated into various liposomes, stealth immunoliposomes, or polymeric nanoparticles as well as for the free compound (Madan and Ghosh 1992; Vasandani et al. 1992; Griffin et al. 1993; Madan et al. 1993; Singh et al. 1994; Ferdous et al. 1998; Shaik et al. 2001; Singh et al. 2001; Tyagi et al. 2013). Notably, this effect was observed not only in the case of free ricin, but also for liposomal formulations, indicating endocytotic uptake of liposomal ricin (Bharadwaj et al. 2006). When comparing different liposomal formulations, major differences were found, with ricin cytotoxicity being dependent on the surface charge and the degree of polyethylene glycol (PEG) substitution, and certain negatively charged liposomes offering maximum cytotoxicity (Rathore and Ghosh 2008; Tyagi et al. 2011; Tyagi et al. 2015). Interestingly, a similar approach of liposome formulation has also been explored for intracellular delivery of anti-ricin A-chain monoclonal antibodies to neutralize ricin toxicity, indicating the potential utility of cell-permeable antibodies for post-exposure treatment of ricin intoxication (Wu et al. 2010). Beyond describing in vitro effects in cell culture, several studies also explored the in vivo use of ricin formulations in mice, demonstrating enhanced cytotoxicity and reduced toxic side effects (Vasandani et al. 1992; Madan et al. 1993; Zhang et al. 1999). For example, prolonged survival was observed in an H-MESO-1 tumor xenograft model, or, in a subset of the treated mice, even the absence of intraperitoneal tumors (Griffin et al. 1993).
Finally, targeted delivery has been explored in the context of ricin as well. While a few papers have looked into the use of the ricin B chain as binding moiety for quantum dot, liposome, or carbon dot targeting (Friede and von Holt 1991; Iversen et al. 2012; Li et al. 2018), most studies have aimed at further improving ricin cytotoxicity and reducing side effects due to more selective cellular uptake. Liposomal ricin with 0.5% Folat-PEG for folate receptor-mediated targeted delivery (Tyagi and Ghosh 2011), peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers (“protocells”) for peptide-directed, cell-specific uptake (Epler et al. 2012), multiwalled carbon nanotubes (MWNTs) for selective delivery of ricin to mamma carcinoma cells overexpressing human epidermal growth factor receptor 2 (HER2/neu; Weng et al. 2009) or virus-like particles (VLPs) of bacteriophage MS2, modified with a peptide (SP4) and a histidine-rich fusogenic peptide (H5WYG) for promoting endosomal escape (Ashley et al. 2011), have been described. These studies followed up on a very early publication on ricin or the ricin A chain encapsulated in liposomes bearing an anti-carcinoembryonic antigen (CEA) antibody, for selective delivery into CEA-expressing tumor cells (Watanabe and Osawa 1987). Finally, a most recent study engineered CXCR4-targeted nanoparticles via self-assembly of the modular protein T22-mRTA-H6, a recombinant version of ricin. Beyond high cytotoxicity in CXCR4+ tumor cells in vitro, profound therapeutic anti-tumor activity in the absence of toxic side effects was also observed in a mouse model of acute myeloid leukemia (Diaz et al. 2018).
Ricin as weapon
As described above, ricin is one of the most potent and lethal biological substances known and is thus also considered as important bioweapon. The broad distribution of the native plant, the broad availability of castor beans as well as the easy process of isolation/extraction of the toxin and its increasing popularity through the Internet make ricin nowadays to an attractive agent in the context of bioterroristic activities (Poelchen and Wirkner 2003; Olsnes 2004; Roxas-Duncan and Smith 2012; Thiermann et al. 2013; Robert Koch Institut 2017).
During World War I and II, the USA and other countries investigated ricin for its military potential as a biological weapon (e.g., bullets and shrapnels coated with ricin, or as “dust cloud”). Ricin is known as “Agent W” (compound W, because of the military symbol W for ricin) (see Olsnes 2004; Roxas-Duncan and Smith 2012; Diac et al. 2017; Patocka 2018 and references therein). According to some reports, ricin has possibly been used as a warfare agent in Iraq in the 1980s and more recently by terrorist organizations (https://emergency.cdc.gov/agent/ricin/facts.asp).
Nowadays, ricin is listed (i) in the Biological Weapons Convention (1972) and (ii) in the Chemical Weapons Convention (1997). More specifically, (i) based on its profound lethality and high availability, ricin has been categorized as a category B biothreat agent (second-highest priority) by the United States (US) Centers for Disease Control and Prevention (CDC). (ii) Ricin is also among the toxic chemicals listed in schedule 1 of the Chemical Weapons Convention (CWC), and in the Biological and Toxin Weapons Convention (BTWC). Its possession, transfer, purification, and use are subject to domestic and international regulations, and are controlled by the Organization for the Prohibition of Chemical Weapons (OPCW) (for references, see Poelchen and Wirkner 2003; Worbs et al. 2011; Roxas-Duncan and Smith 2012; Arnold 2017; https://www.opcw.org/our-work/what-chemical-weapon).
Ricin antibodies and immunization for protection and therapy
There is ongoing research on treatment options after ricin intoxication as well as on potential vaccine candidates (Slominska-Wojewodlzka and Sandvig 2013; Hu et al. 2014; Respaud et al. 2016; Brey et al. 2016; Noy-Porat et al. 2017; Rosenfeld et al. 2017; Toth et al. 2017 and references therein).
Therapeutic strategies after ricin intoxication may include disease-modifying countermeasures, based on anti-ricin antibodies, small molecule compounds, and various combinations of those (immunomodulators and other pharmacological-based treatment options; see Roxas-Duncan and Smith 2012; Hu et al. 2014; Gal et al. 2017). Passive protection with aerosolized anti-ricin immunoglobulin (IgG) has been evaluated as prophylaxis prior to aerosol challenge as well (see Roxas-Duncan and Smith 2012). Neutralizing antibodies are the most promising post-exposure treatment of ricin intoxication, yet so far they have been shown to be effective only when given within several hours post exposure (Noy-Porat et al. 2017). Various monoclonal antibodies have been generated (for review, see Hu et al. 2014), and it has been shown that the use of antibody combinations leads to improved neutralizing capacity in vitro, in vivo and in pre-clinical studies (Prigent et al. 2011). A tri-antibody based cocktail showed high effecacy and very high survival rates (> 70%) when animals were treated as late as 48 h post exposure, and significant protection (> 30%) even at 72 h (Noy-Porat et al. 2017).
A recombinant ribotoxic A-chain subunit with mutations in two residues, named RiVax, has been developed as a specific vaccine against ricin (Smallshaw et al. 2005; Vitetta et al. 2006). RiVax is safe in rabbits and mice, induces high titers of neutralizing antibodies when administered i.m., and had sufficient pre-clinical safety data (Smallshaw et al. 2005). Results from a phase I human trial indicated that RiVax elicited ricin-neutralizing antibodies and was well tolerated in humans (Vitetta et al. 2005; Vitetta 2006). Two closely related RTA-based subunit vaccines, RiVax (see above) and RVEc (a truncated derivative of RTA), are now under further development (for review, see Brey III et al. 2016).
Another potent anti-ricin neutralizing, humanized antibody (hD9) exhibited high efficacy in a female BALB/c mouse model. More specifically, a dose of 5 μg hD9 per mouse (0.25 mg/kg) could rescue 100% of the mice, e.g., after 5 × LD50 (50 μg/kg) ricin challenge (Hu et al. 2014 and references therein).
Gal and co-workers reviewed treatment options upon pulmonary ricin intoxication (Gal et al. 2017). They discuss (i) small-molecule compounds and their potential therapeutic benefit against ricinosis by directly interfering with the toxin or influencing ricin’s intracellular trafficking, as well as (ii) the co-administration of anti-ricin antibodies with immunomodulatory drugs for attenuating lung injury via neutralizing the toxin.
For rapid detection of ricin in environmental and clinical samples as well as in food, analytical methods with high selectivity and sensitivity are required (Kalb and Barr 2009). It is hereby of great importance to distinguish between functionally active vs. denatured ricin, since this has important implications on emergency operating schedules, therapeutic measures, and forensic analysis. This relies on performing functional assays, which also allow for the differentiation between A-chain vs. B-chain activity, or both (see Duracova et al. 2018).
With respect to forensic analysis, ricin detection in clinical samples is particularly difficult. The fact that ricin is denatured by temperatures over 80 °C is important in the context of its analysis, e.g., in food. Furthermore, as mentioned above, agglutinin as well as several toxic proteins and isoforms have been purified from the seeds of Ricinus communis, with amino acid compositions of the isoforms being very similar. Consequently, considerable research efforts have been focused on the development of sensitive methods for the detection of ricin D in complex matrices such as human biological samples, environmental samples, water, and food (Kalb and Barr 2009; Severino et al. 2012; Worbs et al. 2015; Stern et al. 2018; Weber 2018). Possibilities of ricin detection are the lateral flow assay (LFA), the detection of ricinin as accompanying alkaloid in castor bean seeds, polymerase chain reaction (PCR)-based detection of DNA (only applicable in castor bean seeds), or liquid chromatography/mass spectrometry (LC/MS) after protein digestion (Weber and Schulz 2011; Worbs et al. 2015; Duracova et al. 2018; Weber 2018). Furthermore, a variety of immunological methods for ricin detection exist, whereby enzyme-linked immunosorbent assays (ELISA) has been proven to be one of the most versatile techniques (for review, see Severino et al. 2012).
(i) A rapid test based on the immunological detection of ricin in beverages, food, and consumer products is described by Weber and Schulz (2011). The unmodified toxin can be detected with sufficient sensitivity by LFA or ELISA (Weber 2014). When metabolized, ricin is no longer detectable in the body. This also means that, when ricin intoxication is suspected, the environment of the affected person should be analyzed retrospectively with regard to possible sources of ricin uptake. Using LFA, the detection limit is 0.05 mg/L in water and 1–2.5 mg/kg in food. A forensic validation procedure can be performed by peptide analysis (Weber and Schulz 2011).
(ii) For the unambiguous identification of ricin toxin (and the alkaloid marker ricinine) from crude plant materials, special LC/MS and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS methods have been developed (Darby et al. 2001). Nowadays, the combination of different techniques is used (Worbs et al. 2015; Stern et al. 2018). Additionally, a ricin forensic profiling approach based on a complex set of biomarkers including carbohydrates, fatty acids, seed storage proteins in combination with data on ricin, and Ricinus communis agglutinin is developed (Fredriksson et al. 2018).
In samples with complex matrices, MS assays have been found capable of unambiguously identifying ricin and its activity (Kalb et al. 2015). More specifically, Kalb and co-workers reported on the application of MS-based methods for detection, differentiation, and quantitation of ricin and RCA120 in blinded samples, as part of the EQuATox proficiency test (Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk; Kalb et al. 2015). This was the first program for the investigation of qualitative and quantitative data on an international level, aiming at the establishment of an assortment of ricin detection methods which employ well-characterized analytical standards (Kalb et al. 2015).
(iii) Ricinine is used as surrogate marker for ricin exposure and may be more robust than the detection of ricin itself. Due to its chemical stability and extractability in routine extraction procedures in toxicology laboratories, ricinine can be identified by MS-based untargeted toxicology screening (Weber 2014; Lopez Nunez et al. 2017). Ricinin is heat stable and not rapidly metabolized (Johnson et al. 2005; Weber 2014; Weber 2018). Verougstraete and co-workers described an LC-MS/MS method for the detection of ricinine in serum, blood, and urine, validated according to European Medicines Agency (EMA) guidelines and successfully applied to patient samples (Verougstraete et al. 2018). Of note, however, ricinine may also be detectable in the general population since many consumer products contain castor oil. This has been shown, for example, in a study of Pittman and co-workers who characterized urinary ricinine concentrations from 989 individuals presumably unexposed to ricin (Pittman et al. 2013).
Ricinus communis-an interesting and unusual plant
In the light of the high toxicity of the components in the Ricinus communis plant, the “mysterious” ricinus-feeding worm (in the book Jonah, Bible; see also the “Introduction”) has been of special scientific interest considering its resistance. Nowadays, the Israeli tiger moth, Olepa schleini (Lepidoptera, Arctiidae), which regularly infests Ricinus communis fits perfectly to the detailed description of this ricinus feeder mentioned in the Bible (Hausmann and Müller 2006). The leaves of the ricinus plant are also the preferential feed of the Asian population of the silkworm (Samia cynthia ricini) in India (Vijayan et al. 2006). These examples identify Ricinus communis as host and food plant for insects including moths and butterflies as well as some lepidopteran larvae and birds (Roxas-Duncan and Smith 2012), despite its superb toxicity on other larvae of parasites, aphids, gnats, and others. However, the latter aspect is of particular interest with regard to increasing concerns of pesticide accumulation in the environment, prompting researchers to develop safer alternatives. Indeed, some insecticidal lectins may be useful in contributing to the development of integrated pest management strategies with minimal effect(s) on non-target organisms. Plant-derived, biodegradable materials are currently evaluated as an alternative remedy in controlling arthropods of medical and veterinary relevance (Singh and Kaur 2017).
Castor oil, as described above, offers a number of interesting applications and is considered as an option for biodiesel production in several countries. Its importance as a bioenergy and industrial feedstock results from the potential of modifications in fatty acid composition, very high oil yields, a wide range of adaptation, and the plant’s ability to be grown on marginal sites subject to drought and saline conditions (Severino et al. 2012). A life-cycle analysis revealed that the use of castor oil for biodiesel production could offer many advantages like (i) an energy return-on-energy investment (EROEI) of 2.60 and (ii) a positive contribution to climate-change reduction, as revealed by a positive carbon balance (Amouri et al. 2017). In this context, the development of low-ricin or ricin-free castor cultivars (as well as low-ricin, low-ricinine, low-allergen cultivars) is of special interest for commercial castor oil production (Severino et al. 2012). Sousa and co-workers explored the concept of gene knockdown by RNA interference (RNAi) in order to silence the ricin-encoding genes in the endosperm of castor beans, aiming at increased safety of castor bean cultivation for farmers, industrial workers, and society (Sousa et al. 2017). Furthermore, after oil extraction, bio-detoxified castor bean cake is attractive for animal feeding due to its rich content in valuable proteins (Sousa et al. 2017). In contrast, however, since lectins such as ricin play an important role in plant protection against insect pests, the development of ricin-free castor genotypes may increase the risk of pest incidence rates (for review, see Vandenborre et al. 2011).
The need to generate larger and highly standardized amounts of ricin and its modified forms for possible pharmacological applications has led to the development of strategies based on genetic engineering, e.g., the expression of the two full-length polypeptide chains in transgenic tobacco (Sehnke et al. 1994; Sehnke and Ferl 1999). It is interesting to note that the emerging field of nanomedicines, allowing for improved pharmacokinetics and putatively leading to targeted drug delivery, may help in controlling unwanted side effects.
Thus, ricin is perhaps one of the most impressive examples of compounds with superb toxicity on the one hand and therapeutic utility on the other.
Here and in the following, the English translations of the Papyrus Ebers are taken from Ghalioungui (1987).
Biological and Toxin Weapons Convention
Castor bean allergenic fraction
Centers for Disease Control and Prevention
Central nervous system
Chemical Weapons Convention
Enzyme-linked immunosorbent assay
European Medicines Agency
Enhanced permeability and retention
Energy return-on-energy investment
Establishment of Quality Assurance for the Detection of Biological Toxins of Potential Bioterrorism Risk
Joint Food and Agriculture Organization
Food and Drug Administration
Histidine-rich fusogenic peptide
Hepatitis B virus
Human epidermal growth factor receptor 2
International Union of Pure and Applied Chemistry
- LD50 :
Lethal dose 50%
Lateral flow assay
Liquid chromatography/mass spectrometry
Matrix-assisted laser desorption/ionization time-of-flight
Multiwalled carbon nanotubes
Organization for the Prohibition of Chemical Weapons
Pokeweed anti-viral proteins
Polymerase chain reaction
Reactive oxygen species
Ricinus communis agglutinin
Ribosome-inactivating protein type 2
Ricin A chain
Ricin B chain
Vascular lead syndrome
World Health Organization
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Parts of this article on the history of the plant Ricinus communis in the Papyrus Ebers were presented at the Symposium on the Occasion of the 30. Anniversary of the Postgraduate Study Program (PGS) “Toxicology and Environmental Protection” at the University of Leipzig (March 23, 2018). PGS graduation theses by Jörg Pietsch (2004), Gabriele Baranius (2009), and Thorsten Meißner (2017) as well as a study work prepared by Avina Graefe (2012) contributed to this review article and are greatly acknowledged. The authors are grateful to Dr. Jens Grosche (Effigos AG) for providing Fig. 4. The authors also wish to thank Adelgunde Graefe (PGS “Toxicology and Environmental Protection,” University of Leipzig) and Thomas Gruner (Library of the Medical Faculty, University of Leipzig) for their support.
Author contribution statement
HF, RS, and AA wrote the manuscript. HF took the photos, HF and AA created figures and tables. All authors read and approved the manuscript.
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The authors declare that they have no conflicts of interest.
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Suppl. Figure 1
Examples of the world wide distribution of the plant Ricinus communis: (A) La Reunion (on a roadside, up to 10 m high); (B) La Reunion (forest landscape, accompanied by palms); (C) Namibia (Chobe National Park); (D) Madagaskar (Tulear); (E) Vietnam (Hanoi); (F) Ecuador; (G) Costa Rica (Rio Tarcoles); (H) Germany (Botanical Garden, Leipzig). (PNG 7863 kb)
Suppl. Figure 2
Amino acid sequence alignment of ricin in comparison with the type 1 RIPs Gelonin, Trichosanthin, Momordin, Bouganin, Pokeweed anti-viral protein (PAP), Saponin, and Dianthin. Alignment was performed using Clutal Omega (https://www.ebi.ac.uk/services). (PPTX 458 kb) (PPTX 458 kb)
Suppl. Figure 3
Amino acid sequence alignment of ricin and mistletoe lectin-1 from Viscum album. Colors indicate sequence domains encoding for the signal peptide, A-chain, linker, and B-chain. Alignment was performed using Clutal Omega (https://www.ebi.ac.uk/services). Asterisks indicate sequence identities. (PPTX 234 kb)
Suppl. Figure 4
Toxic effects of ricin (PPTX 69 kb)
Suppl. Figure 5
Examples of the different applications of castor oil and its derivatives today (PPTX 69 kb)
Suppl. Table 1
Examples of representative LD50 values of different kinds of toxins (DOCX 26.8 kb)
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Franke, H., Scholl, R. & Aigner, A. Ricin and Ricinus communis in pharmacology and toxicology-from ancient use and “Papyrus Ebers” to modern perspectives and “poisonous plant of the year 2018”. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1181–1208 (2019). https://doi.org/10.1007/s00210-019-01691-6
- Ricinus communis
- Papyrus Ebers
- Castor oil
- Tumor therapy