Others additionally transform the alkaloids into pheromones or utilize them as morphogens. Wellstudied examples have been published for pyrrolizidine and QAs. Vertebrate herbivores (humans included) have effective liver enzymes that can detoxify xenobiotics. Often, substances become hydroxylated, conjugated, and then excreted via the feces or the kidney and urine.
See also: Alkaloids: Toxicology; Chromatography: Thinlayer Chromatography; High-performance Liquid Chromatography; Gas Chromatography; Immunoassays: Radioimmunoassay and Enzyme Immunoassay
M Wink, University of Heidelberg, Heidelberg, Germany
Copyright 2003, Elsevier Science Ltd. All Rights Reserved.
Apparently, most alkaloids play an important role in the ecology of plants or animals. They serve as defense chemicals against herbivores and predators. To a lesser degree they protect against bacteria, fungi, and viruses or provide a means for plant–plant interactions. To be effective defense chemicals, alkaloids must closely interact with specific targets in herbivores, predators, microorganisms, or competing plants, i.e., they must either inhibit or otherwise deregulate important processes that are vital for these organisms. For this purpose the molecular shape of alkaloids has apparently been optimized during a million years of evolution in a process which could be termed ‘evolutionary molecular modeling.’ While the structures of more than 12 000 individual alkaloids have been reported, rather limited knowledge is available for most of them in terms of biological activities and functions. In this chapter the modes of action of the better known alkaloids, especially those found in food plants, are summarized and discussed, considering interactions with organs or complete organisms first and then molecular targets. These interactions are the base for understanding the toxic or antinutritional effects that are observed if humans or animals have ingested alkaloids with their diet.
Bell EA and Charlwood BV (1980) Secondary plant products. In: Encyclopedia of Plant Physiology, vol. 8. Berlin: Springer. Blum MS (1981) Chemical Defenses of Arthropods. New York: Academic Press. Conn EE (1981) Secondary plant products. In: Stumpf PK and Conn EE (eds) The Biochemistry of Plants, vol. 7. New York: Academic Press. Harborne JB (1988) Introduction to Ecological Biochemistry, 3rd edn. London: Academic Press. Hegnauer R (1962–1990) Chemotaxonomie der Pflanzen, vols 1–10. Basel: Birkhauser. ¨ Luckner M (1990) Secondary Metabolism in Microorganisms, Plants, and Animals, 3rd edn. Berlin: Springer. Mothes K, Schutte HR and Luckner M (1985) Biochemistry ¨ of Alkaloids. Weinheim: Verlag Chemie. Roberts MF and Wink M (1998) Alkaloids: Biochemistry, Ecology and Medicinal Applications. New York: Plenum. Robinson T (1981) The Biochemistry of Alkaloids, 2nd edn. Heidelberg: Springer. Rosenthal GA and Berenbaum MR (1991) The chemical participants. In: Herbivores – Their Interactions with Secondary Plant Metabolites, vols 1 and 2. London: Academic Press. Rosenthal GA and Janzen DH (1979) Herbivores: Their Interactions with Secondary Plant Metabolites. London: Academic Press. Rosenthal GA (1982) Plant Nonprotein Amino Acids and Imino Acids. London: Academic Press. Schultes RE and Hofmann A (1980) The Botany and Chemistry of Hallucinogens. Springfield, IL: Charles Thomas. Southon IW and Buckingham J (1989) Dictionary of Alkaloids. London: Chapman & Hall. Wink M (1999) Biochemistry of plant secondary metabolism. In: Annual Plant Reviews, vol. 2. Sheffield, UK: Sheffield Academic Press and CRC Press. Wink M (1999) Function of plant secondary metabolites and their exploitation in biotechnology. In: Annual Plant Reviews, vol. 3, Sheffield, UK: Sheffield Academic Press and CRC Press.
Toxic and Pharmacological Effects at the Organ Level
Many alkaloids are known for their toxic or adverse effects on animals (Table 1). In many cases, only the toxicity of an alkaloid has been reported evidencing substantial interactions, but the exact mode of action has not yet been elucidated or is rather complex, involving several molecular targets and organs. In medicine, alkaloids are employed as local anesthetics, as narcotics, analgesics, as cardiac, uterine and respiratory stimulants, or to raise blood pressure, dilate pupils, and to relax skeletal muscles (Table 2). The use of alkaloids as narcotics and hallucinogens causes major social problems. Ultimately, the toxic and pharmacological effects (Tables 1 and 2) observed must be the result of interactions of alkaloids with molecular targets present in or on cells.
p. 38 Physostigmine Mouse p.17. 9. etc.) is controlled by acetylcholine (Ach) and norepinephrine (noradrenaline).2 Alkaloids derived from phenylalanine/tyrosine Aristolochic acid Mouse i. 152 Ellipticine Mouse i.c.1 Humans p.v. <0. 175.c. 71 Senecionine Rat i.p. 30.p.5 Vincamine Mouse i.v. 6 Rat i. oral. 35 Codeine Mouse s. i.o.5. 1.p.5 Psilocybin Mouse i.v.v. 62 Harman Mouse i.
Modulation of Liver and Kidney Function
Nutrients and xenobiotics (such as secondary metabolites) are transported to the liver after resorption in
.p. 32 Galanthamine Mouse i.
Inhibition of the Digestive Process
Food uptake can be reduced by pungent or bitter taste in the first instance. 940 Chelerythrine Mouse s.p. Many intoxications with alkaloid-containing plants have diarrhea as one of the symptoms.p. s. 0.1 s.v.ALKALOIDS/Toxicology
Table 1 LD50 values of some alkaloids Alkaloid Test system LD50 (mg kg )
Alkaloids derived from tryptophan Brucine Rat p.v.p.c. when there is overstimulation..o.o. 55–67.v. 77 Quinolizidine alkaloids Cytisine Mouse i. or lipids.v. 172 Mouse i. 4.p.o.o. 1.o.p. 5. 1 Cinchonidine Rat i.. 23 Bulbocapnine Mouse p. p. 102.v. 75 Vincristine Mouse i. 413 Canadine Mouse p.p. 0. 56 i.3 Emetine Mouse s. and coordination of bodily functions.p. The next step can be the induction of vomiting. they will be tense or in tetanus.p. 50 Harmine Mouse i.1 Ergometrinea Mouse i.7 Morphine Mouse i. 230 i.5–3.4 Solaninea Mouse i.3. i. 56–106 Berberine Mouse i. 100 Strychnine Agelaius p. 20 Tubocurarine Mouse p.c.c. or hearing).o. p. 16 Thebaine Mouse i. p.v. vision.0 s. 17. s.5 Pyrrolizidine alkaloids Echimidinea Rat i. Alkaloids which activate (so-called parasympathomimetics) or inhibit (parasympatholytics) neuromuscular action are tabulated in Table 3.008
a Encountered in food plants or food items.o. leading to a general paralysis and/or respiratory failure (which is the effect of many of the more toxic alkaloids). 1. 127–137 p. 0. Another way to interfere would be the inhibition of digestive enzymes or of transport proteins for amino acids. muscles will relax.v. 0.v.p. 85 Seneciphylline Rat i. gut).p. 1. 100 p. 138 Monocrotaline Rat i.o. 226–318 Papaverine Mouse i.2 Steroid alkaloids Jervine Mouse i. intraperitoneal.v. would be another activity which negatively influences the digestive system.o.15 Ergotaminea Mouse i.01. 0. A disturbance of metabolism or binding of neurotransmitters and related signal pathways impairs learning and memory.v.p. These compounds are usually considered to be strong poisons (Table 1).3 Protoveratrine Rabbit i.c.v. lungs. 200 Heliotrine Rat i. 45 p. s. 300 Jacobine Rat i. <3. 100 Reserpine Agelaius p. 38–70.4 Tropane alkaloids Atropine Rat p.2 Ergocryptinea Rabbit i. sensory faculties (smell. 8. 9. 263 Quininea Agelaius p.o. 80 Lupaninea N-Methylcytisine Mouse i.48 p. 285 Quinidine Rat i. 36–102 Sanguinarine Mouse s. or the opposite. 17.7 13-Hydroxylupaninea Mouse i. Muscle activity (skeletal. When there is inhibition.o.o.p.v. 350–510 Miscellaneous alkaloids Aconitine Mouse i. 1.v.p.p. or produces euphoric or hallucinogenic effects. 33..p. 0.o. the alkaloid emetine already implies this activity in its name! Causing diarrhea. Any inhibition or overstimulation of neurotransmitter-regulated ion channels will severely influence muscular activity and thus the mobility or organ function (such as heart. 206 Cinchonine Rat i. 300 Colchicine Mouse i.v. intravenous. 0. 27. heart.o.p.v. p. subcutaneous.c. p. constipation.1–0.p.o.p. 0. p.o. 18. i.c. 21. 1
a-Amanitin Arecolinea Caffeinea Coniine Delphinine Maytansine Muscimol Nicotinea Tetrodotoxina
Mouse Mouse Mouse Agelaius Rabbit Rat Rat Agelaius Mouse Mouse
i. 51 Sparteinea Mouse i.8 i.
Central Nervous System and Neuromuscular Junctions
A remarkable number of alkaloids interfere with the metabolism and activity of neurotransmitters in the brain and nerve cells.c.v..1 Samandarine Mouse i. 95 Chelidonine Mouse i.v. which is a common reaction to the ingestion of a number of alkaloids. 42 Veratridine Mouse i.v.p. sugars.v.o.o. 4. 150 Protopine Mouse i.o.v. 750 Cocaine Rat i.o. i.p.o. p.9 Vinblastine Mouse i. p. 0.
mutations. Crotalaria) Ergot alkaloids (from Claviceps purpureus) Activity Conversion to DNA and protein alkylating agent in liver Causing liver cirrhosis. hallucinogenic effects. discussed below. These conjugates are exported via the blood to the kidney for elimination via the urine. The liver is also the main site for the detoxification of xenobiotics. addictive properties Pain and cough depression Local anesthetic Antiarrhythmic properties at heart auricle Antiarrhythmic properties Antiarrhythmic properties at ventricle Stimulation of respiration is followed by respiratory depression. sulfate.)
Scopolamine (Hyoscyamus. which will ultimately reduce their numbers (and fitness as a species). amino acids. gangrenic limps. vincristine (Catharanthus roseus)
Antiparasitic and antimicrobial activity
Antiinflammatory activity Eye treatments
*nAChR. Hyoscyamus. disease named ergotism Local anesthetic. Datura) Tubocurarine (Chondodendron tomentosum) Hyoscyamine (atropine. other malignancies Treatment of lymphomas and other tumors
Aconitine (Aconitum) Morphine (Papaver somniferum) Codeine (Papaver) Cocaine (Erythroxylon coca) Quinidine (Cinchona spp.) Sparteine (Cytisus scoparius) Ajmaline (Rauwolfia serpentina) Nicotine (Nicotina). Increased diuresis would also mean an increased elimination of water and essential ions. recurrent gout Reduces intraocular pressure (glaucoma) Miotic used in the treatment of open-angle glaucoma Treatment of breast and ovary carcinoma. cytisine (Laburnum)
Lobeline (Lobelia spp. The next target is the gestation process itself.
Disturbance of Reproduction
Quite a number of allelochemicals are known to influence the reproductive system of animals. cold. Datura) Papaverine (Papaver somniferum) Berberine (Berberis. used in bronchial asthma Used as a potent poison in antiquity (Socrates) Used in obstetrics Employed in the treatment of bronchial asthma. general paralytic effect Very effective painkiller (used since ancient times). Atropa. emetic drug Anthelmintic activity Antimalarial Treatment of acute gout. Heliotropium. asphyxia or even respiratory failure Stimulant. Antihormonal effects could be achieved by mimicking the structure of sexual hormones. bladder) Smooth-muscle relaxant Intercalates DNA and inhibits parasites and microorganisms Intestinal amoebiasis.) Coniine (Conium maculatum) Constriction of blood vessels Ergot alkaloids (Claviceps purpurea) Ephedrine (Ephedra spp. Both organ systems are affected by a variety of secondary metabolites: pyrrolizidine alkaloids are activated during the detoxification process and are converted into potent carcinogens. long-term exposure to diuresis-inducing compounds would reduce the fitness of a herbivore substantially. such as glucuronic acid. Since Naþ ions are already limited in plant food. causing liver cancer. In the liver the metabolism of carbohydrates. Lipophilic compounds. such as coumarins which dimerize to dicoumarols. used in surgery Antispasmodic at smooth muscles (gastrointestine. sinusitis Dilatator of vessels Block nAChR*.
the intestine. hydrophilic molecule. are also liver toxins. or isoflavones. nicotinic acetylcholine receptor. Many other metabolic inhibitors. which are easily resorbed from the diet.136 ALKALOIDS/Toxicology
Table 2 Pharmacological and medicinal properties of alkaloids Type Poison Alkaloid Pyrrolizidine alkaloids (from Senecio. are often hydroxylated and then conjugated with a polar. Mahonia) Emetine (Cephaelis acuminata) Boldine (Peumus boldo) Quinine (Cinchona succirubra) Colchicine (Colchicum autumnale) Physostigmine (Physostigma venenosum) Pilocarpine (Pilocarpus jaborandi) Taxol (Taxus brevifolia) Vinblastine. or an amino acid.
Many alkaloids are known for their diuretic activity. and lipids and the subsequent synthesis of proteins and glycogen takes place. cancer Cause vasoconstrictions.
epinephrine. Nicotiana Atropa. Hyoscyamus. dopamine. Duboisia Strychnos Chondodendron Conium Several legumes Lobelia Anabasis. other fungi Several legumes Claviceps Pausinystalia.and sesquiterpenes and alkaloids.N-dimethyltryptamine Bufotenine b-carboline alkaloids Mescaline Ergot alkaloids Bulbocapnine Bicuculline Muscimol b-carboline alkaloids Caffeine Theophylline. as do the ergot and lupin alkaloids. Camellia. Datura. other fungi Several plants and toads Virola. Ilex. This dramatic activity has been reported for a number of allelochemicals. theobromine Brucine Strychnine Morphine Physostigmine (eserine) Berberine Coptisine Galanthamine Solanine and other steroid alkaloids Huperzine A Harmaline. dopamine
Molecular Targets of Alkaloids
In the following a number of important cellular molecular targets (Figure 1) have been addressed
. a number of alkaloids are mutagenic and lead to malformation of the offspring or directly to the death of the embryo. g-aminobutyric acid. Banisteriopsis Coffea. quinolizidine analogs. Some alkaloids achieve this by
the induction of uterine contraction. harmine Salsolinol Ephedrine Tetrahydroisoquinoline
Norepinephrine(noradrenaline)/ (adrenaline) epinephrine
Dopamine receptor GABA receptor
Adenosine receptor Glycine receptor Opioid receptor Acetylcholine esterase
Adenosine Glycine Endorphins Acetylcholine
Nicotiana. Peganum Lophophora. histamine Norepinephrine. Aspidosperma Rauwolfia Rauwolfia Papaveraceae Ephedra Claviceps Psilocybe. Clitocybe.
As outlined below. norephedrine Ergot alkaloids Psilocin. including many mono.ALKALOIDS/Toxicology
Table 3 Examples of alkaloids which bind to neurotransmitter receptors and neurotransmitter-degrading enzymes Target Acetylcholine receptors Nicotinic receptor Ligand Alkaloid Occurrence
Nicotine C-toxiferine Tubocurarine Coniine Cytisine and other QA Lobeline Anabasine Hyoscyamine (atropine) Scopolamine Arecoline Pilocarpine Muscarine Sparteine and other QA Ergot alkaloids Yohimbine Rauwolscine Corynanthine Norlaudanosoline Ephedrine. Anadenanthera Banisteriopsis. serotonin. The last step would be premature abortion of the embryo. Inocybe. GABA. other cacti Claviceps Corydalis Dicentra cucullaria and other Corydalis species Amanita Peganum. psilocybine N. Paullinia Theobroma Strychnos Strychnos Papaver somniferum Physostigma venenosum Several Papaveraceae Several Papaveraceae Several Amaryllidaceae Solanum Huperzia serrata Peganum Chenopodiaceae Ephedra Papaveraceae
Monoamine oxidase (MAO)
Norepinephrine. Mandragora Several Solanaceae Areca Pilocarpus Amanita.
DNA replication DNA transcription DNA repair Mitochondrion
Lysosome Cell membrane Cytoskeleton − actin. Biomembranes are almost impermeable for ions and polar molecules. When the neurotransmitter binds. norepinephrine (noradrenaline). a receptor which is part of an ion-channel complex. which can be ion channels. transient ‘holes’ occur in the biomembrane. Communication between cells is especially important for nerve cells. g-aminobutyric acid (GABA). glycine. microtubules
Posttranslational protein modification
Figure 1 Molecular targets of animal cells that are affected by alkaloids. which are present in many members of the Solanaceae (including potatoes and tomatoes). A similar mechanism has been postulated for saponins. to which the steroidal alkaloids may be assigned. Since phospholipids are in a continuous motion. mediate the controlled flux of these compounds across biomembranes.
Biomembranes. a conformational change induces the opening of a Naþ/Kþ channel for
. and neuronal signal transduction
Cells can only operate effectively if their biomembranes (cytoplasmic membrane.. Steroidal alkaloids. histamine. epinephrine (adrenaline). specific membrane proteins. such as solanine and tomatine. rendering the cell leaky. While the steroidal moiety ‘dives’ into the lipophilic interior of the membrane and interacts with the structurally similar cholesterol. pores. malformations have been observed in animal embryos after having been exposed to Solanum alkaloids. internal membranes) are intact. dopamine. Steroidal alkaloids can also interact with other targets. can form complexes with the cholesterol present in biomembranes. among others. a widely distributed group of natural products. the hydrophilic side chain remains outside and binds to external sugar receptors. i. membrane transport. The biomembranes and the complex transport systems are targets of many natural products. As an exchange of these molecules must take place between cells and organs. Signal transduction in the central nervous system and in neuromuscular junctions is mediated by receptor proteins residing in the membrane which are directly or indirectly coupled with ion channels. a
tension easily builds up which leads to membrane disruption. glutamate. serotonin. The neurotransmitters involved include.e. such as neuroreceptors or even with DNA. and acetylcholine (ACh).
which are often affected by alkaloids and other plant toxins. or carrier proteins. Neuroreceptors can be ligand-gated channels.
Table 4 Alkaloids as inhibitors of neurotransmitter uptake (transport into presynapse or into vesicles) Transporter Norepinephrine (noradrenaline) Biogenic amines Alkaloid Reserpine Ephedrine Tetrahydro-b-carboline Salsolinol Tetrahydroisoquinoline Tetrahydropalmatine Cocaine Occurrence Rauwolfia Ephedra Peganum Salsola Papaveraceae Berberidaceae Erythroxylum
Ca2+ channel PRESYNAPSE Vesicle Neurotransmitter
Na+ channel K+ channel POSTSYNAPSE
Figure 2 Signal transduction in excitable synapses. which in turn produces cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP).
G-Protein-linked neuroreceptor Ligand-gated ion channel
. a second messenger. In addition.ALKALOIDS/Toxicology
microseconds. Glutamate (N-methyl-d-aspartate. is hydrolyzed by ACh esterase (Figure 2). several plants produce compounds which are identical to animal neurotransmitters. More abundant are G-protein-coupled neuroreceptors. such as ACh and histamine in stinging hairs of Urtica. or serotonin and dopamine in several species. A prominent one is the muscarinic ACh receptor. enzymes involved in the biosynthesis of a neurotransmitter. These Naþ and Kþ channels constitute another important target for alkaloids (Table 5). NMDA) and GABA receptors are also ligand-gated ion channels. The stimulation of neurotransmitter-activated ion channels leads to a rapid influx of Naþ ions. Its a-subunit dissociates and then activates the enzyme adenylyl cyclase. inducing a conformational change in an adjacent G-protein molecule. They can function therefore as structural analogs. the enzymes which deactivate neurotransmitters after they have bound to a receptor (Table 3) . transport processes. in the case of ACh. the receptor itself through inhibition or overstimulation (Table 3) . and dopamine receptors also belong to this type. The ligand quickly dissociates from the receptor and. The cAMP molecule. When ACh binds. activates protein kinases or Ca2þ channels directly. allowing Naþ ions (the external concentration is about 145 mmol lÀ1) to enter the cell following a concentration gradient (the internal Naþ concentration is between 5 and 15 mmol lÀ1). which are important for the uptake of neurotransmitters into the presynapse or their storage in synaptic vesicles (Table 4) or . the receptor changes its conformation. Targets can be:
. norepinephrine. which are essential for further signal transduction. Quite a number of alkaloids are known whose structures are more or less similar to those of endogenous neurotransmitters. which in turn activates voltage-gated Naþ and Kþ channels.
Kþ-ATPase and Ca2þ-ATPase. Ion gradients and ion fluxes mediated by these channels and pumps are the main elements in the active transport processes. Genista Algae/fish Veratrum Ryania speciosa
Activation Inhibition Activation Inhibition Activation Inhibition Inhibition Inhibition Inhibition Inhibition Activation Inhibition
Naþ channel. such as protein kinase C (which is activated by phorbol esters and the alkaloid chelerythrine) or tyrosine kinase (activating other regulatory proteins or ion channels) Because these targets are almost exclusively found in animals but absent in plants. Since the integrity of DNA is important for the structure and function of rRNAs. sanguinarine. Paulinia Peganum Chelidonium majus Marine seaweeds
cAMP. theobromine Theophylline 1-ethyl-b-carboline Chelerythrine Lyngbyatoxin A Occurrence Annonaceae Leguminosae Peumus Berberidaceae Papaver Coffea.Theobroma Ilex paraguarensis. cyclic adenosine monophosphate. nitidine. key enzymes which produce or inactivate second messengers or amplify the signal can be important targets further down the pathway (Table 6). . Kþ or Ca2þ pumps. Some alkaloids are known to bind or to intercalate with DNA (Table 7). and ClÀ channels) and of active Naþ. phosphodiesterase (inactivating cAMP). and in the skin of certain toads.140 ALKALOIDS/Toxicology
Cells carefully control ion concentrations inside and outside of the cells with the help of specific ion channels (e. adenylyl cyclase (making cAMP). cassaine. They can store these compounds without risk of being intoxicated by their own toxins. Kþ-ATPase found in plants. and solenopsine (from ants) inhibit Naþ. thus impairing the process of replication and transcription. and Ca2þ channels Alkaloid Naþ and Kþ channels Aconitinea Ajmalinea Batrachotoxina Harmalin Protoveratrine A. some insects. coniine. phospholipase (releasing arachidonic acid or inositol phosphates) or . Naþ. Whereas receptor/ion channel interactions represent the initial part of many signal pathways. When anabasine.
0024 0025 0026
Aconitum Rauwolfia Frogs (Dendrobatidae) Peganum Veratrum Cinchona Cinchona Protogonyaulax (algae) Cytisus. in neuronal and neuromuscular signaling. Cardiac glycosides are potent and well-known inhibitors of Naþ. or anagyrine is administered to pregnant cows or sheep. several protein kinases. . hydrophobic molecules which fit between the planar stacks of AT and GC base pairs.
The genetic information of most organisms is mainly encoded in DNA. The effects of DNA-binding or intercalating compounds can be mutations. proteins and enzymes which are important for metabolism. a large proportion of the offspring develop malformations of the
Table 6 Alkaloids modulating enzymes involved in signal transduction Enzyme Adenylyl cyclase Function cAMP formation Alkaloid Annonaine b-carboline-1-propionic acid Isoboldine Tetrahydroberberine Papaverine Caffeine. such as Naþ. These enzymes include:
Table 5 Alkaloids as modulators of Naþ. Camellia. structure and development of an organism.g. Ba Quinidinea Quinine Saxitoxina Sparteinea Tetrodotoxina Veratridinea Ca2þ channels Ryanodine
. capsaicine. It is not surprising that a number of secondary metabolites became selected during evolution which interact with DNA or DNA-processing enzymes.
. Kþ-ATPase. which may result in malformations of newborn animals or in the initiation of cancer. Kþ. Ca2þ. the development of active compounds directed to these targets appears to be advantageous for the plants producing them. DNA is a highly vulnerable target.and RNA-polymerases and DNA topoisomerases. Many of these molecules are planar. Lupinus. A few alkaloids such as harmaline. Kþ. Other alkaloids act on the level of DNA..
. galactosidase. ellipticine.ALKALOIDS/Toxicology
Table 7 Alkaloids interacting with DNA/RNA and related enzymes Target DNA Activity Photoaddition Alkaloid Dictamnine Harman Harmine Pyrrolizidine alkaloids Aristolochic acid Cycasin Ellipticine Quinine. Emetine from Cephaelis ipecacuanha (Rubiaceae) is the most potent plant constituent. tylocrepine.Thalictrum. Boraginaceae Aristolochia Cycads Ochrosia Cinchona Skimmia Berberis. harmin Emetine Fagaronine Hippeastrine Lycorine Camptothecin Berberine Chelidonine Vincristine. quinidine Skimmianine Berberine Coptisine Fagaronine Sanguinarine Olivacine Ergotamine Harmaline. such as jervine and cyclopamine cause the formation of a large central eye. The free base is then readily taken up by the gut cells and transported to the liver. Gloriosa Amanita
DNA topoisomerase I Reverse transcriptase RNA polymerase Transcription
Inhibition Inhibition Inhibition Inhibition
legs – so-called ‘crooked calf disease. a
The respiratory chain and ATP synthesis in mitochondria or photophosphorylation in chloroplasts demand the controlled flux of electrons. homoharringtonine. which are polar compounds that cannot pass biomembranes by simple diffusion. Papaveraceae Chelidonium Catharanthus roseus Colchicum. Other alkaloids with the same ability include harringtonine. Mahonia. Several alkaloids which inhibit protein biosynthesis and are also DNA intercalating substances can induce apoptosis in cells. such as glucosidase. the PA are transformed into alkylating compounds. gramine. especially within the families of Asteraceae and Boraginaceae. These targets seem to be attacked by nicotine.
number of alkaloids have been detected which inhibit protein biosynthesis in vitro. A multitude of enzymes exist in animal cells and several alkaloids have been reported that interfere with at least one of them. these metabolites can alkylate DNA. alpinigenine. vinblastine Colchicine amanitin Occurrence Dictamnus Peganum Peganum Several Asteraceae. cryptopleurine. such as swainsonine or castanospermine. which was probably known to the ancient Greeks and thus led to the mythical figure of the cyclops. narciclasine. Aristolochic acid has a nitro group which can be transformed into reactive intermediates in the intestine. As a result mutations and cancer can be initiated. and a few other alkaloids. tubulosine.
Electron Chains and Other Enzyme Activities
Protein biosynthesis is essential for all cells and thus provides another important target. A recently discovered group of alkaloids are the polyhydroxyalkaloids. In the intestine. and tylopherine. which inhibit hydrolytic enzymes. such as aristolochic acid from Aristolochia and pyrrolizidine alkaloids (PA) which are produced by approximately 3% of the higher plants. hemanthamine.’ Some alkaloids of the monocot Veratrum. There. but become so when they are ‘detoxified’ in the liver: PA are usually present in the plant as their N-oxides. Other alkaloids are known as carcinogens. which covalently bind to DNA and proteins. pseudolycorine. the cyclopean eye. PA-N-oxides are reduced by gut bacteria. lycorine. Pyrrolizidine alkaloids are not carcinogenic in their native form. capsaicine. If resorbed. Chelidonium Several Papaveraceae Rutaceae Several Papaveraceae Aspidosperma Claviceps purpurea Peganum harmala Cephaelis acuminata Rutaceae Hippeastrum Several Amaryllidaceae Camptotheca acuminata Several Berberidaceae. pretazettine. trehalase (trehalose is a sugar found in some beetle cocoons and fungi which is hydrolyzed by trehalase) and mannosidase selectively. sanguinarine.
such as lupanine. In addition. These alkaloids can modulate several receptors of neurotransmitters. Some QA exhibit a prominent cross-reactivity. can also proceed via the above-mentioned mechanisms. thus blocking the signal transduction in nerve cells at a second critical point. phagocytosis. such as anagyrine. and cell movements are also controlled by actin filaments. These compounds may thus inhibit processes such as DNA replication and RNA transcription which are vital for the microorganisms. herbivores will try to develop tolerance to or resistance against the dietary toxins. the polymerization of tubulin is enhanced by taxol. produced by the fatally poisonous toadstool Amanita phalloides. If ingested. But interactions with growth hormones and their metabolism must also be considered.
Target specificity of alkaloids
In general. we can say that Nature has obviously tried ‘to catch as many flies with one clap as possible’ in the selection of alkaloids during evolution. such as ergotamine. fungi. They are bitter for many animals (and plants producing them are therefore avoided as food). such as dopamine. Antimicrobial. If we accept the hypothesis that alkaloids were developed as chemical defense compounds through a process of ‘evolutionary molecular modeling’ the ‘cross-reactivity’ described makes sense: any compound which can interfere with more than one target or with more than one group of adverse organisms is likely to be more effective and thus has a better survival value in general than a more selective allelochemical.
QA. sparteine. Another alkaloid. The stability of biomembranes can be disturbed by steroidal alkaloids and tetrandine. QA. (See Trypsin
. Other targets may be electron chains or just metabolically important enzymes. We can explain these activities through structure similarities between the alkaloid and the different neurotransmitters. are produced by lupins and many members of the Leguminosae. If more than one target is affected by a defense chemical the chances of a herbivore developing specific resistances concomitantly are much smaller than in single-target situations. A few particular QA. QA such as lupanine and sparteine inhibit Naþ and Kþ channels. The assembly of microtubules is inhibited by colchicine. QA exhibit a broad level of toxicity: they interact with ACh receptors (AChR) as agonists. or berberine intercalate with viral and microbial DNA or bind to it. the interactions of a particular alkaloid with a molecular target (as described above) suggest a high degree of specificity. and Phytotoxic Interactions
Circumstantial evidence indicates that some alkaloids protect the producing plant against viruses. are produced by fungi of the genus Claviceps which lives in close contact with many grasses (family Poaceae) such as the cereal Hordeum vulgare. Movements and some transport processes are mediated through either the rapid assembly or disassembly of microtubules. and the bipiperidine alkaloid ammodendrine (which cooccurs with QA in many plants). or cytisine. or ergoclavine. Additionally. These alkaloids thus interrupt cell division. and competing plants.142 ALKALOIDS/Toxicology Cytoskeleton
Microtubules. ranging from vasoconstriction and uterus contraction to hallucinations. are composed of tubulin subunits. like many other alkaloids. which can be observed in plant–plant interactions. cell–cell interactions. and norepinephrine. Cell stability. and dimeric indole alkaloids vinblastine and vincristine (important for chemotherapy of certain cancers). Phytotoxic properties or germination inhibition. the pharmacological action of ergot alkaloids is rather broad. are mutagenic and lead to malformations (see above). As a consequence taxol-induced microtubules are very stable and dividing cells are arrested in the metaphase. The diterpene alkaloid taxol (used in the treatment of ovarian and breast cancer) affects microtubules in the opposite way. Some QA preferentially bind to the nicotinic AChR. A closer look. which are rapidly assembled or disassembled from action monomers. serotonin. Protein biosynthesis in ribosomes is another vulnerable target.
shows that many alkaloids interfere with more than one target.
Ergot alkaloids. As a consequence. however. preventing the addition of actin monomers there. In conclusion. The phenomenon will be explained for two groups of alkaloids: ergot alkaloids and quinolizide alkaloids (QA). attacked by emetine. A number of antimicrobial alkaloids such as sanguinarine. bacteria. which are important for cellular movements. quinine. Cytochalasin B and latrunculin B bind to the plus end of a growing actin filament. vesicle transport in neurons. stabilizes actin filaments and inhibits their depolymerization. whereas others tend more to bind to the muscarinic AChR. phalloidin. ergometrine.
Mechanisms of Allelochemical Activities in Antiviral. occur as complex mixtures in plants. cytisine. or the separation of chromosomes during cell division.
Cereals: Dietary Importance.
E N C Mills. Bray D. However. vol. Ecology and Medicinal Applications. In: Wink M (ed. San Diego: Academic Press. 17–133. New York: Plenum. Antibiotics and Drugs: Uses in Food Production. Rosenthal GA and Berenbaum MR (1991) Herbivores: Their Interactions with Secondary Plant Metabolites. Antibiotics and Drugs: Uses in Food Production. Sheffield: Sheffield Academic Press and CRC Press. pp. San Diego: Academic Press. or isotypes. vol.ALLERGENS
Inhibitors. 2. Saponins. vol. 43. and the body synthesizes larger quantities of IgE. their nomenclature.) Function of Plant Secondary Metabolites and their Exploitation in Biotechnology. Wink M (1993) Allelochemical properties or the raison d’etre of alkaloids. Bristol. UK
Copyright 2003. Ecology. UK A S Tatham. 11. 1–118. environmental agents such as pollen and dietary proteins. Harborne JB (1993) Introduction to Ecological Biochemistry. Lupin. 1. This IgE is directed towards target molecules. Current knowledge of food allergens of plant and animal origin is summarized. New York: Garland. pp.
What is an Allergen?
During the course of normal immune functioning. 3. Wink M (1998) Modes of action of alkaloids.) The Alkaloids. the body produces a number of different forms. IgE can become associated with mast cells. In: Roberts MF and Wink M (eds) Alkaloids. ˆ vol. London: Academic Press. Elsevier Science Ltd.)
See also: Alkaloids: Properties and Determination. and on binding multivalent allergen. 4th edn. 3. which bind to ‘nonself’ molecules. vol. Coffee: Analysis of Coffee Products. it becomes ‘crosslinked’ at the mast cell membrane. of immunoglobulins such as IgA. New York: Plenum. London: Oxford University Press. 301–326. and the properties of proteins thought to predispose them to becoming allergenic. parasites. IgG. Biochemistry. Tomatoes. Norwich. Lewis J.
. Raff M. 2. Potatoes and Related Crops: The Root Crop and its Uses. and Medical Applications. Sheffield: Sheffield Academic Press and CRC Press. in the allergic disease classified as a Type I hypersensitivity reaction. Saponins. San Diego: Academic Press. Institute of Food Research. Amsterdam: Elsevier. Annual Plant Reviews. together with the problems posed to food allergic individuals by ‘hidden’ allergenic ingredients and those that result from cross-contamination in the factory and catering outlets. The impact of postharvest treatments and food processing on allergen activity is described. we do not understand the mechanisms whereby particular allergens elicit an IgE rather than the normal IgG response in certain individuals. Wink M (2000) Interference of alkaloids with neuroreceptors and ion channels. Annual Plant Reviews. vol. Sheffield: Sheffield Academic Press and CRC Press. Ecological and Evolutionary Processes. Wink M and Schimmer O (1999) Modes of action of defensive secondary metabolites. vol. Roberts K and Watson JD (1993) Molecular Biology of the Cell. this antibody repertoire is altered. Annual Plant Reviews. Plant Antinutritional Factors: Characteristics. In: Atta-Ur-Rahman (ed. Mann J (1992) Murder. Tea: Chemistry. 3rd edn. As yet. 3–129. Wink M (1999) Biochemistry of Plant Secondary Metabolism. Roberts MF and Wink M (eds) (1998) Alkaloids: Biochemistry. pp. Wink M (1999) Function of Plant Secondary Metabolites and their Exploitation in Biotechnology. Magic and Medicine. Alkaloids: Properties and Determination. triggering the
This encyclopedia entry describes the nature of food allergens involved in IgE-mediated allergy. These include molecules found in microbial pathogens. and IgE. All Rights Reserved. University of Bristol. In: Cordell GA (ed.
Rosenthal GA and Berenbaum MR (1992) Herbivores: Their Interactions with Secondary Plant Metabolites. The Chemical Participants. pp. IgM. an antibody type normally produced only in response to parasitic infections. which are usually proteinaceous in nature and are known as allergens. Trypsin Inhibitors
Alberts B. and the role that cross-reacting IgE epitopes play in the relationship between pollen and latex allergy and allergies to certain fruits and vegetables is discussed.) Bioactive Natural Products.