Irritant Contact Dermatitis
Plants that cause irritation of the skin on contact are rather common (Nelson et al., 2007). A list of such plants containing their family, genus, and common names can be found in Table 26-3. The trichomes, or barb-like hairs (Fig. 26-1), found on stinging nettles (Urtica species, Urticaceae) puncture skin on contact and release an irritating sap containing a mixture of formic acid, histamine, acetylcholine, and serotonin (Kavalali, 2003). Various species of Urtica can be found all over the world; however, the most dangerous is U. ferox (poisonous tree nettle), which is most common in New Zealand. Exposure has been reported to cause death in humans and animals. Mucuna pruriens (cowhage), which also deploys its toxin via barbed trichomes on contact, may cause pain, itching, erythema, and vesication. Mucinain, contained in the toxin, is the proteinase responsible for causing the pruritus (Southcott and Haegi, 1992).
Stinging hairs of Urtica ferox (nettles).
Table 26-3Selective Plants Producing Contact Dermatitis ||Download (.pdf) Table 26-3 Selective Plants Producing Contact Dermatitis
|BOTANICAL FAMILY ||GENUS SPECIES ||COMMON NAME |
|Amaryllidaceae ||Narcissus ||Narcissus |
|Apocynaceae ||Nerium oleander ||Oleander |
|Bromeliaceae ||Ananas comosus ||Pineapple |
|Asteraceae ||Ambrosia, Aster, Chrysanthemum, Rudbeckia hirta, Tagetes minuta ||Ragweed, aster, chrysanthemum, Blackeyed Susan, Mexican marigold |
|Euphorbiaceae ||Ricinus communis ||Castor bean |
|Fumariaceae ||Dicentra spectabilis ||Bleeding heart |
|Ginkgoaceae ||Ginkgo biloba ||Ginkgo |
|Liliaceae ||Allium cepa ||Onion |
|Myrtaceae ||Eucalyptus globulus ||Eucalyptus |
|Pinaceae ||Abies balsamea ||Balsam fir |
|Saxifragaceae ||Hydrangea ||Hydrangea |
|Solanaceae ||Lycopersicon esculentum, Solanum carolinense, S. turerosum ||Tomato, horse nettle, potato |
|Umbelliferae ||Daucus carota, Heracleum lanatum ||Carrot, cow parsnip |
|Urticaceae ||Urtica dioica, U. urens ||Stinging nettle |
Certain species of Ranunculus (buttercup) contain a compound known as ranunculin, which is enzymatically broken down into the toxin protoanemonin. On contact with skin, protoanemonin found in Anemone (buttercup) is converted to anemonin, which is the irritant directly responsible for the resulting dermatitis. If ingested, protoanemonin may cause severe irritation of the gastrointestinal tract (Kelch et al., 1992).
Damage to the stems or leaves of the genus Euphorbia (Euphorbiaceae, spurge family) causes exudation of a milky latex that contains diterpene esters that are irritating to the skin. Euphorbia marginata (snow-on-the-mountain) is a common plant in the United States that is used in flower arrangements by florists. Dermal contact with its latex can cause skin irritation (Urushibata and Kase, 1991). Also, serious eye irritation has been reported (Frohn et al., 1993). The poinsettia (Euphorbia pulcherrima, Fig. 26-2), which is ubiquitous at holiday times, may cause contact dermatitis (Massermanian, 1998).
Euphorbia pulcherrima (poinsettia).
Allergic Contact Dermatitis
Many people have experienced allergic dermatitis, most frequently from contact with poison ivy. Allergic dermatitis is an actual allergic reaction occurring within the skin as opposed to just a response to the presence of an irritant (Johnson et al., 1972). Due to this immunological component, the severity of the reaction can range widely.
Philodendron scandens (Araceae, arum family) and the toxicodendron group of plants, which contains Rhus radicans (poison ivy, Fig. 26-3), Rhus diversiloba (poison oak), and Rhus vernix (poison sumac), are all known to cause allergic dermatitis. P. scandens is a common houseplant that produces allergenic resorcinols, especially 5-n-heptadecatrienyl resorcinol (Knight, 1991). In the Rhus species the allergen is a fat-soluble substance called urushiol that can penetrate the stratum corneum where it then binds to Langerhans cells in the epidermis. These haptenated cells then migrate to lymph nodes, where T cells are activated resulting in the allergic response (Kalish and Johnson, 1990). Ingestion of Rhus species has been reported to cause generalized dermatitis (Oh et al., 2003). Sap of the mango fruit (Magnifera indica, Anacardiaceae) can also cause allergic dermatitis due to the presence of oleoresins that, with repeated exposure, will cross-react with allergens of poison ivy (Tucker and Swan, 1998).
Toxicodendron radicans (poison ivy).
Alkaloids present in the sap of daffodils, hyacinths, and tulips can sometimes cause irritation. Irritation can also be caused by contact with needle-like crystals of calcium oxalate, also known as raphides, which are present on these plants’ bulbs (Gude et al., 1988). The major culprit is the compound tulipalin-A, which causes “tulip fingers” from handling tulip bulbs (Christensen and Kristiansen, 1999). Tulipalin-A can be found in concentrations up to 2%. A safe threshold for this allergen is considered to be 0.01% (Hausen et al., 1983). Table 26-4 contains more plants that cause irritation due to oxalates.
Table 26-4Selective Plants Causing Gastrointestinal Irritation Due to Release of Raphides of Oxalates ||Download (.pdf) Table 26-4 Selective Plants Causing Gastrointestinal Irritation Due to Release of Raphides of Oxalates
|BOTANICAL FAMILY ||SCIENTIFIC NAME ||COMMON NAME |
|Amaranthaceae ||Halogeton glomeratus ||Saltlover, halogeton |
|Araceae ||Alocasia macrorrhiza ||Giant taro |
| ||Anthurium andreanum ||Flamingo Lily |
| ||Caladium bicolor ||Caladium |
| ||Dieffenbachia sp. ||Dumbcane |
| ||Epipremnum sp. ||Pothos, Devil’s Ivy |
| ||Monstera sp. ||Shingle plant, Swiss Cheese plant |
| ||Philodendron scandens ||Philodendron |
| ||Scindapsus aureus, Pothosaureus ||Marble queen |
| ||Spathiphyllum sp. ||Peace Lily |
| ||Syngonium podophyllum ||Arrowhead plant |
|Chenopodiaceae ||Spinacia oleracea ||Spinach |
|Commelinaceae ||Tradescantieae sp. ||Spiderworts |
|Onagraceae ||Fushsia sp. ||Fuchsia |
|Oxalidaceae ||Oxalis sp. ||Wood sorrel |
|Palmae ||Caryotamitis ||Fishtail palm |
|Polygonaceae ||Rheum rhaponticum ||Rhubarb |
|Portulacaceae ||Portulaca sp. ||Purslane |
|Vitaceae ||Parthenocissus quinquefolia ||Virginia creeper |
| ||Parthenocissus triscupidata ||Boston ivy, Japanese creeper |
“Latex-fruit syndrome” is the result of cross-sensitivity to latex in rubber gloves and some fruits. Hevea brasiliensis (the latex tree) produces prohevein, a chitin-binding polypeptide that is also found in several plants. Hevein, a 43–amino acid N-terminal fragment of prohevein, is the major binding component (Kolarich et al., 2005). Individuals who are allergic to rubber latex may become sensitized to fruits containing a chitinase with a hevein-like domain, such as banana, kiwi, tomato, and avocado (Blanco et al., 1999).
Lichens, such as species of Usnea and Cladonia, are known to cause dermatitis due to the production of usnic acid (a benzofuran) and related acids (Aalto-Korte et al., 2005). Usnic acid has also been implicated in hepatotoxicity following use of certain nonprescription weight loss supplements (Han et al., 2004).
Dermatitis does not necessarily have to be caused by skin contact. Consumption of Hypericum perforatum (St. John’s wort) by animals can lead to serious dermatitis and even may be life threatening. The toxic agent is hypericin (a bianthraquinone) that, once ingested and dispersed systemically, causes photosensitization of the animal’s skin. On exposure to sunlight, edematous lesions form on areas of skin that are not protected by hair such as the nose and ears (Sako et al., 1993). Photosensitization caused by St. John’s wort in humans is a rare occurrence; however, an increased response to therapeutic exposure to ultraviolet therapy has been reported (Beattie et al., 2005).
“Hay fever” or rhinitis from inhalation of plant pollens is a seasonal problem for many individuals. A chromosomal association in these individuals is under investigation (Blumenthal et al., 2006). Trees, grasses, and weeds are all responsible to contributing to airborne pollen. Grass species Poa and Festuca are major contributors along with pollen from several weed genera in the Asteraceae (eg, mugwort, Artemisia vulgaris, in Europe, and ragweed, Ambrosia sp., in North America, Fig. 26-4). The common denominator in the various pollen allergens is the conserved binding domain known as profiling, which is also found in birch pollen (Hirschwehr et al., 1998). Asthma and rhinitis have been linked to individuals who are exposed to cascara sagrada (Rhamnus purshiana) (Giavina-Bianchi et al., 1997), or workers in greenhouses in which bell peppers are growing (Groenewoud et al., 2006).
Ambrosia psilostachya (western ragweed).
Workers who process peppers have a significantly increased incidence of coughing when specifically handling Capsicum annuum (sweet pepper) and Capsicum frutescens (red pepper). These two types of peppers produce the major irritants capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) and dihydrocapsaicin (Surh et al., 1998). Specific nerves in the airway have been found to be capsaicin-sensitive, which leads to the irritation and cough (Blanc et al., 1991).
The pneumotoxin, 4-ipomeanol, is produced in sweet potato roots (Ipomea batatas, Convolvulaceae) by the mold Fusarium solani. 4-Ipomeanol is activated by human cytochrome P450s to an intermediate that binds to DNA (Alvarez-Diez and Zheng, 2004). In cattle and rabbits, the major P450 activator is CYP4B1 found in the lung that results in pneumonia. In the mouse, CYP4B1 is most abundant in the kidneys that results in renal toxicity and in humans multiple subsets of liver P450 enzymes are responsible for activating 4-ipomeanol (Baer et al., 2005).
Ingestion of a toxic plant can cause irritation of the gastrointestinal tract often resulting in nausea, vomiting, and diarrhea. Many different compounds produced by plants can cause mild to severe versions of these effects. A list of plants known to cause these effects is provided in Table 26-5. Ingestion of ripe tung nuts (Aleurites fordii) causes abdominal pain, vomiting, and diarrhea. Outbreaks of poisoning are most likely to occur in children (Lin et al., 1996).
Table 26-5Selective Plants Causing Gastrointestinal Irritation ||Download (.pdf) Table 26-5 Selective Plants Causing Gastrointestinal Irritation
|COMMON NAME ||SCIENTIFIC NAME ||TOXIC PART ||TOXIN |
|Amaryllis ||Hippeastrum equestre ||Bulb ||Lycorine |
|Barberry ||Berberis vulgaris ||Root ||Protoberberine and other isoquinoline alkaloids |
|Boxwood ||Buxus sp. ||Leaves, stems ||Steroidal alkaloids |
|Buttercup ||Ranunculus sp. ||All parts ||Ranunculin, protoanemonin |
|Crown of thorns ||Euphorbia milii ||All parts ||Resiniferatoxin |
|Daffodil ||Narcissus ||All, especially bulb ||Lycorine, narcissin, phenanthridine alkaloids |
|English Ivy ||Hedera helix ||All parts ||Hederin from hederagenin |
|Euonymus ||Euonymus sp. ||All parts ||Alkaloids |
|Hyacinth ||Hyacinthus orientalis ||Bulb ||Calcium oxalate, lycorine |
|Iris ||Iris ||Bulb ||Irritant resin |
|Mayapple ||Podophyllum peltatum ||Green fruit, roots ||Podophyllotoxin |
|Mistletoe ||Phoradendron flavescens ||Berries, other parts ||Phoratoxin |
|Pokeweed ||Phytolacca americana ||All parts ||Phytolaccatoxin, related triterpines |
|Purging nut ||Jatropha curcas ||Seeds ||Jatrophin (curcin) (toxalbumin) |
|Tung nut ||Aleurites fordii ||Nut ||Derivative of phorbol, saponins, toxalbumins |
|Wiseria ||Wisteria sinensis ||Pods ||Wistarine (glycoside) |
Toxic quinolizidine alkaloids are found in buffalo beans, also known as buffalo peas (Thermopsis rhombifolia), which grow naturally in the western United States. Ingestion by children causes nausea, vomiting, dizziness, and abdominal discomfort (McGrath-Hill and Vicas, 1997). Also, consumption by livestock of the mature plant with seeds has been reported to be fatal.
Nuts from Aesculus hippocastanum (horse chestnut, Fig. 26-5) and Aesculus glabra (Ohio buckeye) contain a glucoside called esculin. Ingestion by humans causes gastroenteritis, which increases in severity with the number of nuts consumed. Fortunately, esculin is poorly absorbed by the gastrointestinal tract of humans and its systemic effects are usually limited. However, in cattle, esculin may be hydrolyzed in the rumen resulting in release of the aglycone to cause systemic effects. This can lead to nervous system stimulation—marked by a stiff-legged gait and, in severe poisoning, tonic seizures with opisthotonus (Casteel et al., 1992). The triperpene saponin b-aescin in horse chestnut seed extract may have value in treatment of venous insufficiency in humans (Siebert et al., 2002).
Podophyllotoxin is found in Podophyllum peltatum (May apple, Berberidaceae) especially in its foliage and roots. In low doses, mild purgation occurs; however, overdose results in nausea and severe paroxysmal vomiting (Frasca et al., 1997). By binding microtubules, podophyllotoxin blocks mitosis from proceeding. This has made podophyllotoxin of interest for treatment of cancer (Schacter, 1996).
Found in the bulbs of Colchicum autumnale (autumn crocus, Liliaceae), colchicine blocks the formation of microtubules ultimately preventing successful mitosis. Ingestion of these bulbs causes severe gastroenteritis (nausea, vomiting, diarrhea, and dehydration). Severe poisoning can result in confusion, hematuria, neuropathy, renal failure and cardiotoxicity (Mendis, 1989).
Protein Synthesis Inhibition
The family Euphorbiaceae contains several genera that are known to be very toxic. The castor bean (Ricinus communis, Fig. 26-6) is an ornamental plant that produces seeds that, if eaten by children or adults, causes no symptoms of poisoning for several days after ingestion. Gradually, gastroenteritis develops resulting in some loss of appetite, with nausea, vomiting, and diarrhea. If a fatal dose is ingested, the gastroenteritis becomes extremely severe and is marked by persistent vomiting, bloody diarrhea, and icterus followed by death within six to eight days. A fatal dose for a child can be as few as five seeds and may be as low as 20 seeds for an adult. However, fatality occurs in less than 10% of ingestions when a “fatal” dose is consumed owing to the fact that the toxic protein is largely destroyed during digestion. The toxic agents are two lectins found in the beans: ricin I and ricin II of which ricin II is more toxic. Ricin II is made up of an A-chain and a B-chain. The B-chain is responsible for helping the A-chain get inside the cell. It binds to a terminal galactose residue on the cell membrane that then allows for the A-chain to be endocytosed (Wu et al., 2006). Once inside, the A-chain inactivates the 60s ribosomal subunit of cells by catalytic depurination of an adenosine residue within the 28s rRNA (Bantel et al., 1999), thereby blocking protein synthesis.
Ricinus communis (castor bean plant).
The seeds of Abrus precatorius (jequirity bean, Leguminosae) contain lectins known as abrins. Abrin-a, one of four isoabrins produced by the plant, has the highest inhibitory effect on protein synthesis and consists of an A-chain and a B-chain (Tahirov et al., 1994). Similar to ricin, the A-chain directly inhibits protein synthesis while the B-chain is responsible for getting the A-chain inside the cell (Ohba et al., 2004). The LD50 of abrin when injected in mice is less than 0.1 μg/kg making abrin one of the most toxic substances known.
Plants that produce only A-chains are not nearly as toxic as those that pair them with a B-chain. Young shoots of pokeweed (Phytolacca americana, Phytolaccaceae, Fig. 26-7) can be ingested without toxicity; however, consumption of mature leaves and berries may cause nausea and diarrhea. The plant produces three isozymes of single-chain lectins that are capable of inhibiting protein synthesis in cells. However, these do not readily pass through a cells membrane but are capable of doing so with the help of a virus (Monzingo et al., 1993).
Phytolacca americana (pokeweed).
Wisteria floribunda (Leguminosae) is a common ornamental climbing vine that develops seeds in the fall. Ingestion of these seeds can cause severe gastroenteritis. Just a few seeds can produce headache, nausea, and diarrhea within hours, followed by dizziness, confusion, and hematemesis (Rondeau, 1993). The toxic agent is a lectin that binds N-acetylglucosamine on mammalian neurons.
The best known cardioactive glycoside is Digitalis purpurea (foxglove, Scrophulariaceae, Fig. 26-8). However, others exist in the lily family, such as squill (Scilla maritima), which contains scillaren, and lily of the valley (Convallaria majalis), which contains convallatoxin in the bulbs, that have actions similar to digitalis. Also, milkweeds (Asclepias species, Asclepiadaceae) contain glycosides (Roy et al., 2005). Other cardiotoxic plants can be found in Table 26-6. The cardiac glycoside desglucouzarin in Asclepias asperula, like digitalis, inhibits Na+,K+-ATPase (Abbott et al., 1998). Two plants in the Apocynaceae (oleander family) also contain cardioactive glycosides. Thevetia peruviana (yellow oleander) is a common ornamental plant in the United States whose seeds contain the highest concentration of cardiac glycosides. The fatal dose to an adult is eight to 10 seeds (Prabhasankar et al., 1993). Clinical aspects of oleander toxicosis in sheep have been described (Aslani et al., 2004). Also, oleander poisoning may not be fatal (Pietsch et al., 2005).
Digitalis purpurea (common foxglove).
Table 26-6Selective Plants Causing Cardiotoxicity ||Download (.pdf) Table 26-6 Selective Plants Causing Cardiotoxicity
|COMMON NAME ||SCIENTIFIC NAME ||TOXIC PART ||TOXIN |
|Azalea ||Rhodendron sp. ||All ||Grayanotoxins |
|Death camus ||Zigadenus ||All ||Zygadenine, veratrine |
|Foxglove ||Digitalis sp. ||Leaves, seeds ||Digitalis glycosides |
|Larkspur ||Delphenium ambiguum ||All ||Delphinine |
|Lily of the valley ||Convallaria majalis ||All ||Convallarin, convallamarin |
|Milkweed ||Asclepias sp. || ||(Hydroxycinnamoyl) desglucouzarin |
|Monkshood ||Aconitum sp. ||Leaves, roots, seeds ||Aconitine, aconine |
|Oleander ||Nerium oleander ||All ||Oleandrin, oleandrosine |
Actions on Cardiac Nerves
Toxic alkaloids found in Veratrum viride (American hellebore, Liliaceae, Fig. 26-9), Veratrum album (European hellebore), and Veratrum californicum cause nausea, emesis, hypotension, and bradycardia on ingestion. Veratrum album has been used for centuries to “slow and soften the pulse.” The mixture of alkaloids includes protoveratrine, veratramine, and jervine that affects the heart by causing a repetitive response to a single stimulus resulting from prolongation of the sodium current (Jaffe et al., 1990). The bulbs of the wild camas (Zigadenus paniculatus and other species of Zigadenus, Liliaceae) contain Veratrum-like alkaloids (Peterson and Rasmussen, 2003).
Veratrum viride (American hellebore).
Aconitum species, which have been used in western and eastern medicine for centuries, produce the toxic alkaloids aconitine, mesaconitine, and hypoaconitine. Poisoning may occur on ingestion but severity varies with the concentration of the alkaloids, which depends on species, place of origin, time of harvest, and processing procedures (Chan et al., 1994). Along with cardiac arrhythmias and hypotension, ingestion causes gastrointestinal upset and neurological symptoms. The alkaloids work by causing a prolonged sodium current with slowed repolarization in cardiac muscle (Peper and Trautwein, 1967) and in nerve fibers (Murai et al., 1990).
Grayanotoxins are produced exclusively by several genera of Ericaceae (heath family) and in particular they are found in Rhododendron ponticum (Fig. 26-10; Onat et al., 1991) R. macrophyllum (Casteel and Wagstaff, 1989), and Kalmia angustifolia (Burke and Doskotch, 1990). Ingestion of honey contaminated with grayanotoxins, brought there by bees, can produce a severe reaction called “mad honey poisoning.” The poisoning resembles aconitine poisoning in that there is bradycardia, hypotension, oral parasthesia, and gastrointestinal upset. Severe poisoning can result in respiratory depression and eventually loss of consciousness. Grayanotoxins bind to sodium channels in cardiac and muscle cells resulting in increased sodium conductance (Maejima et al., 2002).
Rhododendron ponticum (rhododendron).
American mistletoe (Phoradendron flavescens) and European mistletoe (Viscum album, Loranthaceae) are members of the same family and both produce a toxin that is marked for its effect on the cardiovascular system. Both phoratoxin (produced by American mistletoe) and viscotoxin (produced by European mistletoe) cause hypotension, vasoconstriction of the vessels in skin and skeletal muscle, and bradycardia resulting from negative inotropic actions on heart muscle. Phoratoxin is only one-fifth as active as the viscotoxins (Rosell and Samuelsson, 1988). Although serious poisoning from the plants is rare, it is possible to induce anaphylaxis with repeated injections of mistletoe extract (Bauer et al., 2005).
Ingestion of the fungus Claviceps purpurea (ergot), which grows on grains that are used for food, causes vasoconstriction. The “ergot gene cluster” is required for production of ergot alkaloids (Coyle and Panaccione, 2005; Haarmann et al., 2005). Ergot poisoning was called “St. Anthony’s fire” due to the blackened appearance of the limbs of some victims. In extreme cases, the vasoconstriction was severe enough that gangrene would develop in the extremities. Abortion in pregnant women is also common after ingestion of ergot-contaminated grains. Acremonium coenophialum, a fungus which grows on the grass tall fescue (Festuca arundinacea), produces some ergot alkaloids. Grazing cattle that ingest the contaminated grass develop “fescue toxicosis” (Blodgett, 2001; Hill et al., 1994). This condition results in decreased weight gain, decreased reproductive performance, and increased peripheral vasoconstriction. Pulmonary infection from Acremonium strictum has been noted in a horse (Pusterla et al., 2005).
Pyrrolizidine alkaloids can be found in Senecio (groundsel, Asteraceae) and within four genera of Boraginaceae, Echium (bugloss), Cynoglossum (hound’s tongue), Heliotropium (heliotrope), and Symphytum (comfrey) Altamirano et al., 2005; Mei et al., 2005. Ingestion of significant concentrations of these alkaloids causes liver damage in the form of hepatic veno-occlusive disease associated with lipid peroxidation (Bondan et al., 2005). Cattle that graze on grass contaminated with Senecio have been found to develop hepatitis that can progress to death if allowed to continue grazing. Human deaths have also been reported in several countries and in Afghanistan, an epidemic of hepatic veno-occlusive disease arose from consumption of a wheat crop contaminated by Heliotropium (Tandon et al., 1978). The liver damage caused by ingestion clinically appears to be similar to cirrhosis and some hepatic tumors that can easily be mistaken to be the source of the disease (McDermott and Ridker, 1990). Consumption of these plants leads to a form of the Budd–Chiari syndrome, which is hallmarked by portal hypertension and obliteration of the small hepatic veins. Human consumption can occur from drinking “comfrey tea” that contains Symphytum (Rode, 2002). There are species differences in metabolism of the pyrrolizidine alkaloids (Huan et al., 1998).
Lantana camara (Verbenaceae), a shrub native to Jamaica, has been shown to poison livestock, particularly in India. Cattle grazing on the plant develop bile-related disorders including cholestasis and hyperbilirubinemia. Several triterpenoids have been isolated from the plant and in particular lantadene A (22-β-angeloyloxy-3-oxo-olean-12-en-28-oic acid) has been shown to be hepatotoxic (Sharma et al., 1991).
Most nonedible mushrooms may cause mild discomfort and are not life threatening; however, repeated ingestion of the false morel, Gyromitra esculenta, has been found to cause hepatitis (Michelot and Toth, 1991). The toxin gyromitrin is generally inactivated by boiling. Most fatal poisonings related to wild mushrooms are from ingestion of different species within Amanita, Galerina, and Lepiota (Karlson-Stiber and Persson, 2003). The dangerousness of Amanita phalloides (Fig. 26-11) and Amanita ocreata is why they are named “death cap” and “death angel,” respectively. Two types of toxins, phalloidin and amatoxins, can be found within A. phalloides. Phalloidin is capable of binding actin in muscle cells; however, it is not readily absorbed during digestion, which limits its harmful effects (Cappell and Hassan, 1992). Unfortunately, α-, β-, and γ-amanitins are readily absorbed due to being molecularly much smaller than phalloidin. Of the amatoxins, α-amanitin is the most toxic as it inhibits protein synthesis in hepatocytes by binding to RNA polymerase II (Jaeger et al., 1993). In addition to liver, intestinal mucosa and kidneys are also affected and serious clinical signs develop about three days after ingestion. In cases of severe poisoning, a liver transplant may be required. Amatoxin-a irreversibly inhibits acetylcholinesterase (Hyde and Carmichael, 1991).
Amanita phalloides (death cap).
Fumonisin toxins are produced by the fungus Fusarium that is known to grow on corn. Consumption of contaminated corn by horses leads to equine leukoencephalomalacia that is marked by lethargy, ataxia, convulsions, and ultimately death (Norred, 1993). The liver is the most affected organ in many species including horses, pigs, chickens, and rats (Riley et al., 1994). Ingestion in humans has been suggested to be associated with esophageal cancer (Yoshizawa et al., 1994). Fumonisins are diesters of propane-1,2,3-tricarboxylic acid and a pentahydroxyicosane containing a primary amino acid (Gurung et al., 1999) that is similar to sphingosine. This similarity is responsible for their toxicity as they block the enzymes involved in sphingolipid biosynthesis (Norred, 1993). In contrast, mycoestrogenic zearalenone induces CYP3A enzymes (Ding et al., 2006). Aflatoxin B1 has been shown to form guanine adducts and induce apoptosis in human hepatocytes (Reddy et al., 2006).
The bracken fern (P. aquilinum), which is extremely common worldwide, is the only higher plant known to be carcinogenic in animals under natural feeding conditions. The commonest bladder tumors in cattle are epithelial and mesenchymal neoplasms (Kim and Lee, 1998). Ptaquiloside, a norsesquiterpene glucoside, is the known carcinogen present in the fern and it has been found to alkylate adenines and guanines of DNA (Rasmussen et al., 2003; Shakin et al., 1999). Bovine consumption of bracken fern has been shown to significantly increase chromosomal aberrations (Lioi et al., 2004). Also, evidence has been found that consumption of young bracken fern shoots by humans is associated with cancers of the mouth and throat (Alonso-Amelot and Avendano, 2002).
Kidney Tubular Degeneration
Species of Xanthium (cocklebur, Asteraceae) have been found to contain the toxin carboxyatractyloside, which causes microvascular hemorrhages in multiple organs (Turgut et al., 2005). Livestock poisoning has been noted to cause the outward signs of depression and dyspnea; however, internally the toxin causes tubular degeneration and necrosis in the kidney and centrilobular necrosis in the liver (del Carmen Mendez et al., 1998).
Consumption of the mushroom species Cortinarius has been found to cause acute renal failure but different species vary widely in toxicity and, therefore, edibility. In an investigation of a series of 135 poisonings related to Cortinarius ingestion, where death occurred in almost 15% of the cases, renal biopsy showed acute degenerative tubular lesions with inflammatory interstitial fibrosis (Bouget et al., 1990). Cortinarius orellanus and C. rubellus (Fig. 26-12) contain the deadly toxin orellanin, which triggers renal failure. Table 26-7 lists the common and scientific names and toxins for selective plants that are capable of inducing nephrotoxicity.
Cortinarius rubellus (deadly webcap).
Table 26-7Selective Plants Producing Nephrotoxicity ||Download (.pdf) Table 26-7 Selective Plants Producing Nephrotoxicity
|COMMON NAME ||SCIENTIFIC NAME ||PART ||TOXIN |
|Autumn crocus ||Colchicum autumnale ||Bulb ||Colchicine |
|Castor bean ||Ricinus communis ||All ||Ricin, recinine |
|Daphne ||Daphne mezereum ||Leaves, fruits ||Daphnin, mezerein (diterpenoid) |
|Impila ||Callilepis laureola ||Tubers ||Atractyloside |
|Mushrooms ||Amanita phalloides ||All ||Amatoxin |
| ||Cortinarius sp. ||All ||Orellanine |
|Water hemlock ||Cicuta maculata ||Roots ||Cicutoxin |
Fungal infections in sweet clover (Melilotus alba) have been found to produce dicumarol, a coumarin derivative that is a potent anticoagulant. Deaths in cattle have been reported and are caused by hemorrhages (Puschner et al., 1998).
Argemone (Papaveraceae), a species of poppy, produces sanguinarine, a benzophenanthridine alkaloid that is known to intercalate DNA and have carcinogenic potential (Das et al., 2005). Studies in mice have shown that a single low dose of argemone oil increases chromosomal aberrations in bone marrow cells (Ansari et al., 2004).
Cyanogens are found in a wide variety of plants including the kernels of apples, cherries, and peaches. The highest concentrations are found in the seeds of the bitter almond, Prunus amygdalus var amara. However, small children are susceptible to amygdalin poisoning if they consume enough peach (Prunus persica) kernels. Fortunately, the concentration present in seeds of apples is low enough that they are unlikely to cause a problem. Metabolism of amygdalin releases hydrocyanic acid that binds to the ferric ion in methemoglobin, which, if severe enough, results in cyanide poisoning with death from asphyxiation (Bromley et al., 2005; Jorgensen et al., 2005; Rosling, 1993). Severe cyanide poisoning can occur with so-called vitamin supplements (O’Brien et al., 2005).
Cassava produced from Manihot esculenta (Euphorbiaceae) is a major food source for some regions of Africa. The raw root contains a cyanogenic glucoside linamarin that is removed during processing of the root for human consumption. Unfortunately, local processing may be inadequate and that can lead to ingestion of linamarin. Chronic ingestion has been suggested to be the cause of epidemics of konzo, a form of tropical myelopathy with sudden onset of spastic paralysis (Tylleskar et al., 1992).
The common and scientific names for selective plants that produce neurotoxins can be found in Table 26-8. Within the family Apiaceae, which contains carrots, the fleshy tubers of Cicuta maculata (water hemlock, Fig. 26-13) produce neurotoxic cicutoxin (a C17-polyacetylene). Consumption of a single tuber can result in fatal poisoning, characterized by tonic–clonic convulsions, owing to the cicutoxin binding to GABA-gated chloride channels (Uwai et al., 2000).
Cicuta maculate (water hemlock).
Table 26-8Selective Plants Producing Neurotoxicity ||Download (.pdf) Table 26-8 Selective Plants Producing Neurotoxicity
|COMMON NAME ||SCIENTIFIC NAME ||PART ||TOXIN ||MECHANISM |
|Acacia tree || ||Seeds || || |
|Alga || |
|All || || |
|Betel nut || ||Nut || || |
|Buckthorn; Coyotillo || ||Seeds, leaves || || |
|Chrysanthemum || ||Seeds || || |
|Deadly nightshade || ||Berries || || |
|Fly agaric mushroom || ||All || || |
|Rhododendron || ||Leaves || || |
|Ryania || ||Stems || || |
|Poison nut tree || ||All, especially seeds || || |
|Tobacco || ||Leaves || || |
Members of the mint family (Labiatae) such as pennyroyal (Hedeoma), sage (Salvia), and hyssop (Hyssopus) are well known for their essential oils containing monoterpenes. Ingestion of these monoterpenes in concentrations much higher than those used for flavoring can cause tonic–clonic convulsions. In particular, menthol is a selective modulator of inhibitory ligand-gated channels (Hall et al., 2004).
Certain species within Strychnos (Loganiaceae) produce strychnine and brucine, which are known to cause increased CNS stimulation by blocking glycine-gated chloride channels. Strychnos nux vomixa, a small tree native to India, produces seeds that have been implicated in cases of unintentional poisoning (Wang et al., 2004).
Red algae (Digenia simplex) under certain conditions can proliferate rapidly leading to the notorious beach vacating “red tide” and producing kainic acid. Kainic acid may be ingested by humans who eat filter-feeding mussels that have eaten red algae. Acute symptoms are most notably gastrointestinal distress, headache, hemiparesis, confusion, and seizures. Severe exposure can result in severe memory deficits and sensorimotor neuropathy (Teitelbaum et al., 1990). Isodomoic acid from Nitzschia sp. has seizure-inducing properties (Kotaki et al., 2005).
The fungi Amanita muscaria (fly agaric, Fig. 26-14) and Amanita pantherian (panther agaric) produce the excitatory amino acid ibotenic acid (isoxazole amino acid) and its derivative muscimol that is neurotoxic (Li and Oberlies, 2005). Poisoning produces central nervous system depression, ataxia, hysteria, and hallucinations. Myoclonic twitching and seizures sometimes develop (Benjamin, 1992). Other genera of fungi have been marked for their hallucinogenic actions, notably Psilocybe, which contains psilocin and psilocybin (Tsujikawa et al., 2003).
Amanita muscaria (fly agaric).
Willardiine, an agonist on glutamate receptors, has been isolated from Acacia willardiana, Acacia lemmoni, Acacia millefolia, and Mimosa asperata (Gmelin, 1961) and causes excitation of the nervous system. Seeds from the legume Lathyrus sativus (grass pea) also contain an excitatory amino acid known as β-N-oxalyl-l-α,β-diaminopropionic acid (Warren et al., 2004). Consumption of seeds over long periods can cause lathyrism to develop. Affected individuals have corticospinal motor neuron degeneration with severe spastic muscle weakness and atrophy but little sensory involvement (Spencer et al., 1986). Thiocyanate from linamarin can stimulate neuronal glutamate receptors, leading to degeneration of corticospinal motor pathways (Spencer, 1999).
Motor Neuron Demyelination
Karwinskia humboldtiana is a shrub found in the southwestern United States, Mexico, and Central America that produces anthracenones in its seeds. Both human and livestock poisonings have been known to occur (Bermundez et al., 1986). Several days following ingestion, ascending flaccid paralysis develops with demyelination of large motor neurons in the legs and eventually leads to bulbar paralysis in fatal cases (Martinez et al., 1998). In addition to neurotoxicity, the anthracenones in Karwinskia, especially peroxisomicine A2, cause lung atelectasis, emphysema, and massive liver necrosis. Inhibition of catalase in peroxisomes has been proposed as the mechanism of cell toxicity (Martinez et al., 1997).
The legumes Swainsonia cansescens, Astragalus lentiginosus (spotted locoweed), and Oxytropis sericea (locoweed) produce a toxic indolizidine alkaloid called swainsonine. These weeds can be accidentally consumed by grazing cattle causing aberrant behavior with hyperexcitability and locomotor difficulty (James et al., 1991). In fatal cases there is cytoplasmic foamy vacuolation of cerebellar neurons. Swainsonine causes marked inhibition of liver lysosomal and cytosomal α-mannosidase and Golgi mannosidase II resulting in abnormal accumulation of brain glycoproteins and mannose-rich oligosaccharides that ultimately causes cell death (Tulsiani et al., 1988). Embellisia fungi from locoweed produce a locoweed-like toxicosis (McLain-Romero et al., 2004).
Certain mushrooms of the genera Inocybe, Clitocybe, and Omphalatus contain significant amounts of muscarine, the principal neurotransmitter in the parasympathetic nervous system. Consumption of one these species results in extreme parasympathetic activation resulting in diarrhea, sweating, salivation, and lacrimation (de Haro et al., 1999).
Atropine, l-hyoscyamine, and scopolamine are belladonna alkaloids that can be found in varying concentrations in several genera of Solanaceae such as Datura stramonium (jimson weed, Fig. 26-15), Hyoscyamus niger (henbane), Atropa belladonna (deadly nightshade, Fig. 26-16), and Duboisia myoporoides (pituri). These alkaloids all effectively block the muscarinic receptor, essentially turning off the parasympathetic drive at the target organ. This explains why tachycardia, dry mouth, dilated pupils, and decreased gastrointestinal motility all occur on ingestion of these toxins (Smith et al., 1991). Consumption of grains contaminated with seeds from Datura sp produce poisoning typical of belladonna alkaloids (van Muers et al., 1992). Of the three alkaloids, scopolamine is the most potent; however, sizable doses of l-hyoscyamine or atropine can produce similar effects. Large doses can cause confusion, bizarre behavior, hallucinations, and subsequent amnesia and in severe intoxication, tachycardia may be completely absent (Caksen et al., 2003).
Datura stramonium (jimson weed).
Atropa belladonna (deadly nightshade).
The seeds of Solanum dulcamara (bittersweet), which are used in flower arrangements, contain the glycoalkaloid solanine that on ingestion causes tachycardia, dilated pupils, and hot and dry skin—symptoms similar to atropine poisoning (Ceha et al., 1997).
Capsaicin found in C. annuum (sweet pepper) and C. frutescens (red pepper) causes a burning sensation on vanilloid-type (VR1) sensory receptors. It also desensitizes the transient potential vanilloid 1 receptor (TRPV1) of sensory endings of C-fiber nociceptors to stimuli, a property which has therapeutic use in treating chronic pain (Szalcsany, 2002). Capsaisin also can relax ileal smooth muscle (Fujimoto et al., 2006). Fortunately, desensitization produced by capsaicin is not due to cell death (Dedov et al., 2001). Polygodial, a sesquiterpene found in Polygonum hydropiper, also desensitizes the TRPV1 (Andre et al., 2006), whereas resiniferatoxin activates TRVP1 (Raisinghani et al., 2005). Pyrethum from chrysanthemum flowers blocks sodium channels in the insect nervous system (McGovern and Bakley, 1999).
Skeletal Muscle and Neuromuscular Junction
Anabasine, an isomer of nicotine, is present in Nicotiana glauca (tree tobacco, Solanaceae) and produces prolonged depolarization of the junction after a period of excessive stimulation. Consumption of N. glauca leaves can result in flexor muscle spasm and gastrointestinal irritation, followed by severe, generalized weakness, and respiratory compromise (Mellick et al., 1999). Curare, which is used as a poison placed on the tips of arrows, is also a potent neuromuscular blocking agent and is obtained from tropical species of Strychnos toxifera and Chondrodendron tomentosum. Anabaena flosaquae, a species of alga, can produce under the right conditions a neurotoxin anatoxin A that is known to be fatal. Anatoxin A, ingested by animals that drink pond water with the alga present, depolarizes and blocks the animal’s nicotinic and muscarinic acetylcholine receptors, which can cause death from respiratory arrest within minutes to hours (Short and Edwards, 1990).
Delphinium barbeyi (tall larkspur, Ranunculaceae), which grows naturally in the western United States, contains methyllycaconitine. Ingestion of the toxin by cattle results in muscle tremors and ataxia followed by prostration and can ultimately lead to respiratory arrest in fatal cases. Methyllycaconitine is similar to curare in that it has a high affinity for the acetylcholine receptor at the neuromuscular junction. Physostigmine has been used successfully as an antagonist to treat some cases of methyllycaconitine poisoning (Pfister et al., 1994).
Certain species of Thermopsis produce seeds that contain quinolizidine alkaloids. Human poisoning from eating the seeds is rare, but cases have been reported in young children who experienced abdominal cramps, nausea, vomiting, and headache lasting up to 24 hours (Spoerke et al., 1988). Livestock grazing on Thermopsis montana (false lupine, mountain goldenbanner, Fig. 26-17) develop locomotor depression and recumbency due to areas of necrosis in skeletal muscle that have been found on autopsy (Keeler and Baker, 1990).
Thermopsis montana (mountain goldenbanner).
Consumption of Cassia obtusifolia (sicklepod, Leguminosae) seeds by livestock causes a degenerative myopathy in cardiac and skeletal muscle. Extracts of C. obtusifolia have been found to inhibit NADH-oxidoreductase in bovine and swine mitochondria in vitro (Lewis and Shibamoto, 1989).
White snakeroot (Ageratina altissima, Asteraceae, Fig. 26-18), a common plant in the central and western United States, can be accidentally eaten by grazing cattle. On ingestion, the cattle exhibits tremors and humans who drink the milk of an affected cow can get “milk sickness” (Beier et al., 1993). The toxic effects are attributed to tremetone, a benzofuran, which blocks gluconeogenesis from lactate, resulting in acidosis, tremor, and ultimately death (Polya, 2003).
Ageratina altissima (white snakeroot).
Bone and Tissue Calcification
Consumption of Solanum malacoxylon (Solanaceae) by sheep and cows can cause a marked decrease in bone calcium and calcification of the entire vascular system due to the presence of a water-soluble vitamin D–like substance. In severe cases other organs can also be affected such as the lungs, joint cartilage, and kidney.
Consumption of Cestrum diurnum (day-blooming jasmine, Solanaceae) and Cestrum laevigatum has been found to cause hypercalcemia and soft tissue calcification in grazing cattle (Durand et al., 1999) and chickens (Mello and Habermehl, 1992), which is due to the presence of a dihydroxyvitamin D3 glycoside in the leaves (Durand et al., 1999). Hay that has been contaminated with C. laevigatum caused a marked centrilobular and midzonal hepatic necrosis in goats (Peixato et al., 2000).
Reproduction and Teratogenesis
Besides its actions on the nervous system, swainsonine, the active alkaloid in the legumes Astragalus and Oxytropus, also causes abortions in pregnant livestock that accidentally ingest locoweeds (Bunch et al., 1992).
Foliage and seeds of Leucaena leucocephala, Leucaena glauca, and Mimosa pudica contain a toxic amino acid, mimosine, which on ingestion by cattle leads to uncoordinated gait, goiter, and reproductive disturbances including infertility and fetal death (Kulp et al., 1996). Mimosine has been found to arrest the cell cycle in late G1 phase that helps explain its toxic effects (Perry et al., 2005).
Lectins present in bitter melon seeds (Momordica charantia, Curcurbitaceae) have antifertility, abortifacient, and embryotoxic actions on ingestion. Components of the lectins known as momorcharins are known to induce midterm abortion in humans (Wang and Ng, 1998).
Caulophyllum thalictroides (blue cohosh, Berberidaceae) contains a toxin known as caulophylline that is teratogenic in rats (Kennelly et al., 1999) and herbal preparations of blue cohosh have been used to terminate pregnancy (Jones and Lawson, 1998). In fact, nicotine toxicity may result from blue cohosh use as an abortifacient (Rao and Hofman, 2002).
Ingestion of V. californicum (California false hellebore, Liliaceae, Fig. 26-19) by pregnant sheep is known to cause malformations in its offspring that can include cyclopia, exencephaly, and microphthalmia. As with most teratogens, the severity of malformations depends on what developmental stage the fetus is in at the time of exposure. Limb defects are common with exposure during the fourth to fifth week of gestation; fetal stenosis of the trachea will occur with ingestion on days 31 to 33 (Omnell et al., 1990). Many other species of animals are susceptible to V. californicum poisoning including cows, goats, chickens, rabbits, rats, and mice (Omnell et al., 1990), hamsters (Gaffield and Keeler, 1993), lambs (Keeler, 1990), and rainbow trout embryos (Crawford and Kocan, 1993). The toxic alkaloid called jervine causes teratogenesis by blocking cholesterol synthesis that, among other things, prevents a proper response of fetal target tissue to the sonic hedgehog gene (Shh). Shh has an important role in proper developmental patterning of head and brain, and blocking cholesterol synthesis has been shown experimentally to cause a loss of midline facial structures (Cooper et al., 1998).
Veratrum californicum (California false hellebore).
Pregnant cattle grazing on Lupinus caudatus and Lupinus formosus (lupines, Leguminosae), N. glauca (tree tobacco, Solanaceae), and Conium maculatum (poison hemlock, Solanaceae) have been found to experience a myriad of fetal deformations if ingestion occurs during a sensitive gestational period. The toxic alkaloids in these plants are anagyrine (L. caudatus), ammodendrine (L. formosus), anabasine (N. glauca), and coniine (C. maculatum, Forsyth et al., 1996). It is thought that these alkaloids depress fetal movements that can lead to malformations (Lopez et al., 1999).