Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

Подождите немного. Документ загружается.

Others additionally transform the alkaloids into

pheromones or utilize them as morphogens. Well-

studied examples have been published for pyrroli-

zidine and QAs. Vertebrate herbivores (humans

included) have effective liver enzymes that can detox-

ify xenobiotics. Often, substances become hydroxy-

lated, conjugated, and then excreted via the feces or

the kidney and urine.

See also: Alkaloids: Toxicology; Chromatography: Thin-

layer Chromatography; High-performance Liquid

Chromatography; Gas Chromatography;

Immunoassays: Radioimmunoassay and Enzyme

Immunoassay

Further Reading

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 Biochemis-

try, 3rd edn. London: Academic Press.

Hegnauer R (1962–1990) Chemotaxonomie der Pflanzen,

vols 1–10. Basel: Birkha

user.

Luckner M (1990) Secondary Metabolism in Microorgan-

isms, Plants, and Animals, 3rd edn. Berlin: Springer.

Mothes K, Schu

tte 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 Chem-

istry 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 metabol-

ism. 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.

Toxicology

M Wink, University of Heidelberg, Heidelberg,

Germany

Background

0001Apparently, 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 appar-

ently been optimized during a million years of evolu-

tion in a process which could be termed ‘evolutionary

molecular modeling.’

0002While the structures of more than 12 000 individ-

ual 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, espe-

cially 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.

Toxic and Pharmacological Effects at the

Organ Level

0003Many 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.

0004In medicine, alkaloids are employed as local anes-

thetics, 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.

0005Ultimately, the toxic and pharmacological effects

(Tables 1 and 2) observed must be the result of inter-

actions of alkaloids with molecular targets present in

or on cells.

134 ALKALOIDS/Toxicology

Central Nervous System and Neuromuscular

Junctions

0006A remarkable number of alkaloids interfere with the

metabolism and activity of neurotransmitters in the

brain and nerve cells. A disturbance of metabolism or

binding of neurotransmitters and related signal path-

ways impairs learning and memory, sensory faculties

(smell, vision, or hearing), and coordination of bodily

functions, or produces euphoric or hallucinogenic

effects.

0007Muscle activity (skeletal, heart, etc.) is controlled

by acetylcholine (Ach) and norepinephrine (nor-

adrenaline). Any inhibition or overstimulation of

neurotransmitter-regulated ion channels will severely

influence muscular activity and thus the mobility or

organ function (such as heart, lungs, gut). When there

is inhibition, muscles will relax; when there is over-

stimulation, they will be tense or in tetanus, leading to

a general paralysis and/or respiratory failure (which

is the effect of many of the more toxic alkaloids).

Alkaloids which activate (so-called parasympathomi-

metics) or inhibit (parasympatholytics) neuromuscu-

lar action are tabulated in Table 3. These compounds

are usually considered to be strong poisons (Table 1).

Inhibition of the Digestive Process

0008Food uptake can be reduced by pungent or bitter taste

in the first instance. The next step can be the induc-

tion of vomiting, which is a common reaction to

the ingestion of a number of alkaloids; the alkaloid

emetine already implies this activity in its name!

Causing diarrhea, or the opposite, constipation,

would be another activity which negatively influences

the digestive system. Many intoxications with

alkaloid-containing plants have diarrhea as one of

the symptoms. Another way to interfere would be

the inhibition of digestive enzymes or of transport

proteins for amino acids, sugars, or lipids.

Modulation of Liver and Kidney Function

0009Nutrients and xenobiotics (such as secondary meta-

bolites) are transported to the liver after resorption in

tbl0001 Table 1 LD

values of some alkaloids

Alkaloid Test system LD

(mgkg

1

)

Alkaloids derived from tryptophan

Brucine Rat p.o. 1

Cinchonidine Rat i.p. 206

Cinchonine Rat i.p. 152

Ellipticine Mouse i.v. 1.2

Ergocryptine

Rabbit i.v. 1.1

Ergometrine

Mouse i.v. 0.15

Ergotamine

Mouse i.v. 62

Harman Mouse i.p. 50

Harmine Mouse i.v. 38

Physostigmine Mouse p.o. 4.5

Psilocybin Mouse i.v. 285

Quinidine Rat i.v. 30; p.o. 263

Quinine

Agelaius p.o. 100

Reserpine Agelaius p.o. 100

Strychnine Agelaius p.o. 6

Rat i.v. 0.9

Vinblastine Mouse i.v. 9.5

Vincamine Mouse i.v. 75

Vincristine Mouse i.p. 5.2

Alkaloids derived from phenylalanine/tyrosine

Aristolochic acid Mouse i.v. 38–70; p.o. 56–106

Berberine Mouse i.p. 23

Bulbocapnine Mouse p.o. 413

Canadine Mouse p.o. 940

Chelerythrine Mouse s.c. 95

Chelidonine Mouse i.v. 35

Codeine Mouse s.c. 300

Colchicine Mouse i.v. 4.1

Humans p.o. 0.1–0.3

Emetine Mouse s.c. 32

Galanthamine Mouse i.v. 8; p.o. 18.7

Morphine Mouse i.v. 226–318

Papaverine Mouse i.v. 27.5; s.c. 150

Protopine Mouse i.p. 36–102

Sanguinarine Mouse s.c. 102; i.v. 16

Thebaine Mouse i.p. 20

Tubocurarine Mouse p.o. 33.2

Steroid alkaloids

Jervine Mouse i.v. 9.3

Protoveratrine Rabbit i.p. <0.1

Samandarine Mouse i.p. <3.4

Solanine

Mouse i.p. 42

Veratridine Mouse i.p. 1.4

Tropane alkaloids

Atropine Rat p.o. 750

Cocaine Rat i.v. 17.5

Pyrrolizidine alkaloids

Echimidine

Rat i.p. 200

Heliotrine Rat i.p. 300

Jacobine Rat i.p. 138

Monocrotaline Rat i.p. 175, p.o. 71

Senecionine Rat i.p. 85

Seneciphylline Rat i.p. 77

Quinolizidine alkaloids

Cytisine Mouse i.v. 1.7

13-Hydroxylupanine

Mouse i.p. 172

Lupanine

Mouse i.p. 80

N-Methylcytisine Mouse i.v. 21; i.p. 51

Sparteine

Mouse i.p. 55–67; p.o. 350–510

Miscellaneous alkaloids

Aconitine Mouse i.v. 0.17; p.o. 1

a-Amanitin Mouse i.p. 0.1

Arecoline

Mouse s.c. 100

Caffeine

Mouse p.o. 127–137

Coniine Agelaius p.o. 56

Delphinine Rabbit i.p. 1.5–3.0

Maytansine Rat s.c. 0.48

Muscimol Rat p.o. 45

Nicotine

Agelaius p.o. 17.8

Mouse i.v. 0.3; p.o. 230

Tetrodotoxin

Mouse i.p. 0.01; s.c. 0.008

Encountered in food plants or food items.

i.p., intraperitoneal; i.v., intravenous; p.o., oral; s.c., subcutaneous.

ALKALOIDS/Toxicology 135

the intestine. In the liver the metabolism of carbo-

hydrates, amino acids, and lipids and the subsequent

synthesis of proteins and glycogen takes place. The

liver is also the main site for the detoxification of

xenobiotics. Lipophilic compounds, which are easily

resorbed from the diet, are often hydroxylated and

then conjugated with a polar, hydrophilic molecule,

such as glucuronic acid, sulfate, or an amino acid.

These conjugates are exported via the blood to the

kidney for elimination via the urine. Both organ

systems are affected by a variety of secondary metab-

olites: pyrrolizidine alkaloids are activated during the

detoxification process and are converted into potent

carcinogens, causing liver cancer. Many other meta-

bolic inhibitors, discussed below, are also liver toxins.

Many alkaloids are known for their diuretic activity.

Increased diuresis would also mean an increased elim-

ination of water and essential ions. Since Na

ions are

already limited in plant food, long-term exposure

to diuresis-inducing compounds would reduce the

fitness of a herbivore substantially.

Disturbance of Reproduction

0010Quite a number of allelochemicals are known to

influence the reproductive system of animals, which

will ultimately reduce their numbers (and fitness as a

species). Antihormonal effects could be achieved by

mimicking the structure of sexual hormones, such as

coumarins which dimerize to dicoumarols, or isofla-

vones. The next target is the gestation process itself.

tbl0002 Table 2 Pharmacological and medicinal properties of alkaloids

Type Alkaloid Activity

Poison Pyrrolizidine alkaloids (from Senecio,

Heliotropium, Crotalaria)

Conversion to DNA and protein alkylating

agent in liver

Causing liver cirrhosis, mutations, cancer

Ergot alkaloids (from Claviceps purpureus) Cause vasoconstrictions, hallucinogenic

effects, gangrenic limps; disease named

ergotism

Aconitine (Aconitum) Local anesthetic, general paralytic effect

Analgesics Morphine (Papaver somniferum) Very effective painkiller (used since ancient

times); addictive properties

Codeine (Papaver) Pain and cough depression

Cocaine (Erythroxylon coca) Local anesthetic

Cardiac stimulants Quinidine (Cinchona spp.) Antiarrhythmic properties at heart auricle

Sparteine (Cytisus scoparius) Antiarrhythmic properties

Ajmaline (Rauwolfia serpentina) Antiarrhythmic properties at ventricle

Respiratory stimulant Nicotine (Nicotina), cytisine (Laburnum) Stimulation of respiration is followed by

respiratory depression, asphyxia or even

respiratory failure

Lobeline (Lobelia spp.) Stimulant; used in bronchial asthma

Coniine (Conium maculatum) Used as a potent poison in antiquity

(Socrates)

Constriction of blood vessels Ergot alkaloids (Claviceps purpurea) Used in obstetrics

Ephedrine (Ephedra spp.) Employed in the treatment of bronchial

asthma,

cold, sinusitis

Scopolamine (Hyoscyamus, Atropa, Datura) Dilatator of vessels

Muscle relaxant Tubocurarine (Chondodendron tomentosum) Block nAChR*; used in surgery

Hyoscyamine (atropine, Hyoscyamus, Atropa, Datura) Antispasmodic at smooth muscles

(gastrointestine, bladder)

Papaverine (Papaver somniferum) Smooth-muscle relaxant

Antiparasitic and antimicrobial

activity

Berberine (Berberis, Mahonia) Intercalates DNA and inhibits parasites and

microorganisms

Emetine (Cephaelis acuminata) Intestinal amoebiasis, emetic drug

Boldine (Peumus boldo) Anthelmintic activity

Quinine (Cinchona succirubra) Antimalarial

Antiinflammatory activity Colchicine (Colchicum autumnale) Treatment of acute gout, recurrent gout

Eye treatments Physostigmine (Physostigma venenosum) Reduces intraocular pressure (glaucoma)

Pilocarpine (Pilocarpus jaborandi) Miotic used in the treatment of open-angle

glaucoma

Cytostatic treatment Taxol (Ta x u s br e vif olia ) Treatment of breast and ovary carcinoma;

other malignancies

Vinblastine, vincristine (Catharanthus roseus) Treatment of lymphomas and other tumors

*nAChR, nicotinic acetylcholine receptor.

136 ALKALOIDS/Toxicology

As outlined below, a number of alkaloids are muta-

genic and lead to malformation of the offspring or

directly to the death of the embryo. The last step

would be premature abortion of the embryo. This

dramatic activity has been reported for a number of

allelochemicals, including many mono- and sesquiter-

penes and alkaloids. Some alkaloids achieve this by

the induction of uterine contraction, as do the ergot

and lupin alkaloids.

Molecular Targets of Alkaloids

0011In the following a number of important cellular

molecular targets (Figure 1) have been addressed

tbl0003 Table 3 Examples of alkaloids which bind to neurotransmitter receptors and neurotransmitter-degrading enzymes

Target Ligand Alkaloid Occurrence

Acetylcholine receptors

Nicotinic receptor Acetylcholine Nicotine Nicotiana, Duboisia

C-toxiferine Strychnos

Tubocurarine Chondodendron

Coniine Conium

Cytisine and other QA Several legumes

Lobeline Lobelia

Anabasine Anabasis, Nicotiana

Muscarinic receptor Acetylcholine Hyoscyamine (atropine) Atropa, Hyoscyamus,

Datura, Mandragora

Scopolamine Several Solanaceae

Arecoline Areca

Pilocarpine Pilocarpus

Muscarine Amanita, Inocybe, Clitocybe,

other fungi

Sparteine and other QA Several legumes

Adrenergic receptors Norepinephrine(noradrenaline)/

(adrenaline) epinephrine

Ergot alkaloids Claviceps

Yohimbine Pausinystalia, Aspidosperma

Rauwolscine Rauwolfia

Corynanthine Rauwolfia

Norlaudanosoline Papaveraceae

Ephedrine, norephedrine Ephedra

Serotonin receptor Serotonin Ergot alkaloids Claviceps

Psilocin, psilocybine Psilocybe, other fungi

N,N-dimethyltryptamine Several plants and toads

Bufotenine Virola, Anadenanthera

b-carboline alkaloids Banisteriopsis, Peganum

Mescaline Lophophora, other cacti

Dopamine receptor Dopamine Ergot alkaloids Claviceps

Bulbocapnine Corydalis

GABA receptor GABA Bicuculline Dicentra cucullaria and other

Corydalis species

Muscimol Amanita

b-carboline alkaloids Peganum, Banisteriopsis

Adenosine receptor Adenosine Caffeine Coffea, Camellia, Ilex, Paullinia

Theophylline, theobromine Theobroma

Glycine receptor Glycine Brucine Strychnos

Strychnine Strychnos

Opioid receptor Endorphins Morphine Papaver somniferum

Acetylcholine esterase Acetylcholine Physostigmine (eserine) Physostigma venenosum

Berberine Several Papaveraceae

Coptisine Several Papaveraceae

Galanthamine Several Amaryllidaceae

Solanine and other

steroid alkaloids Solanum

Huperzine A Huperzia serrata

Monoamine oxidase (MAO) Norepinephrine, dopamine,

serotonin, histamine

Harmaline, harmine Peganum

Salsolinol Chenopodiaceae

Ephedrine Ephedra

Catechol-O-methyltransferase Norepinephrine, epinephrine,

dopamine

Tetrahydroisoquinoline Papaveraceae

QA, quinolizidine analogs; GABA, g-aminobutyric acid.

ALKALOIDS/Toxicology 137

which are often affected by alkaloids and other plant

toxins.

Biomembranes, membrane transport, and neuronal

signal transduction

0012 Cells can only operate effectively if their biomem-

branes (cytoplasmic membrane, internal membranes)

are intact. Biomembranes are almost impermeable for

ions and polar molecules. As an exchange of these

molecules must take place between cells and organs,

specific membrane proteins, which can be ion chan-

nels, pores, or carrier proteins, mediate the controlled

flux of these compounds across biomembranes. The

biomembranes and the complex transport systems are

targets of many natural products.

0013 Steroidal alkaloids, such as solanine and tomatine,

which are present in many members of the Solanaceae

(including potatoes and tomatoes), can form com-

plexes with the cholesterol present in biomembranes.

While the steroidal moiety ‘dives’ into the lipophilic

interior of the membrane and interacts with the struc-

turally similar cholesterol, the hydrophilic side chain

remains outside and binds to external sugar receptors.

Since phospholipids are in a continuous motion, a

tension easily builds up which leads to membrane

disruption; transient ‘holes’ occur in the biomem-

brane, rendering the cell leaky. A similar mechanism

has been postulated for saponins, a widely distributed

group of natural products, to which the steroidal

alkaloids may be assigned. Steroidal alkaloids can

also interact with other targets, such as neurorecep-

tors or even with DNA; malformations have been

observed in animal embryos after having been

exposed to Solanum alkaloids.

0014Communication between cells is especially import-

ant for nerve cells. Signal transduction in the central

nervous system and in neuromuscular junctions is

mediated by receptor proteins residing in the mem-

brane which are directly or indirectly coupled with

ion channels. The neurotransmitters involved in-

clude, among others, norepinephrine (noradrenaline),

epinephrine (adrenaline), serotonin, dopamine, hista-

mine, glycine, g-aminobutyric acid (GABA), glutam-

ate, and acetylcholine (ACh).

0015Neuroreceptors can be ligand-gated channels, i.e.,

a receptor which is part of an ion-channel complex.

When the neurotransmitter binds, a conformational

change induces the opening of a Na

channel for

Receptors

Transporters

Signal transduction

Electron transport

Protein biosynthesis

DNA replication

DNA transcription

DNA repair

RNA

Posttranslational

protein modification

Mitochondrion

Ion channels

Enzymes

Cell membrane

Cytoskeleton

− actin, microtubules

Lysosome

Nucleus

fig0001 Figure 1 Molecular targets of animal cells that are affected by alkaloids.

138 ALKALOIDS/Toxicology

microseconds, allowing Na

ions (the external con-

centration is about 145 mmol l

1

) to enter the cell

following a concentration gradient (the internal Na

concentration is between 5 and 15 mmol l

1

). The

ligand quickly dissociates from the receptor and, in

the case of ACh, is hydrolyzed by ACh esterase

(Figure 2). Glutamate (N-methyl-d-aspartate,

NMDA) and GABA receptors are also ligand-gated

ion channels.

0016 More abundant are G-protein-coupled neuro-

receptors. A prominent one is the muscarinic ACh re-

ceptor; norepinephrine, serotonin, and dopamine

receptors also belong to this type. When ACh binds,

the receptor changes its conformation, inducing a

conformational change in an adjacent G-protein mol-

ecule. Its a-subunit dissociates and then activates the

enzyme adenylyl cyclase, which in turn produces

cyclic adenosine monophosphate (cAMP) from

adenosine triphosphate (ATP). The cAMP molecule,

a second messenger, activates protein kinases or Ca

2þ

channels directly.

0017 Quite a number of alkaloids are known whose

structures are more or less similar to those of

endogenous neurotransmitters. They can function

therefore as structural analogs. In addition, several

plants produce compounds which are identical to

animal neurotransmitters, such as ACh and histamine

in stinging hairs of Urtica, or serotonin and dopamine

in several species. Targets can be:

0018the receptor itself through inhibition or overstimu-

lation (Table 3)

0019the enzymes which deactivate neurotransmitters

after they have bound to a receptor (Table 3)

0020transport processes, which are important for the

uptake of neurotransmitters into the presynapse

or their storage in synaptic vesicles (Table 4)or

0021enzymes involved in the biosynthesis of a neuro-

transmitter.

The stimulation of neurotransmitter-activated ion

channels leads to a rapid influx of Na

ions, which

in turn activates voltage-gated Na

and K

channels,

which are essential for further signal transduction.

These Na

and K

channels constitute another

important target for alkaloids (Table 5).

PRESYNAPSE

Acetylcholine

esterase

Vesicle

Neuroreceptor

channel

POSTSYNAPSE

Ligand-gated ion channel

G-Protein-linked neuroreceptor

Neurotransmitter

transporter

channel

Neurotransmitter

fig0002 Figure 2 Signal transduction in excitable synapses.

tbl0004Table 4 Alkaloids as inhibitors of neurotransmitter uptake

(transport into presynapse or into vesicles)

Transporter Alkaloid Occurrence

Norepinephrine Reserpine Rauwolfia

(noradrenaline) Ephedrine Ephedra

Biogenic amines Tetrahydro-b-carboline Peganum

Salsolinol Salsola

Tetrahydroisoquinoline Papaveraceae

Tetrahydropalmatine Berberidaceae

Dopamine Cocaine Erythroxylum

ALKALOIDS/Toxicology 139

0022 Cells carefully control ion concentrations inside

and outside of the cells with the help of specific ion

channels (e.g., Na

,Ca

2þ

, and Cl



channels) and

of active Na

or Ca

2þ

pumps, such as Na

-ATPase and Ca

2þ

-ATPase. Ion gradients and ion

fluxes mediated by these channels and pumps are

the main elements in the active transport processes,

in neuronal and neuromuscular signaling. Cardiac

glycosides are potent and well-known inhibitors of

-ATPase found in plants, some insects,

and in the skin of certain toads. A few alkaloids

such as harmaline, nitidine, sanguinarine, capsaicine,

cassaine, and solenopsine (from ants) inhibit Na

-ATPase.

0023 Whereas receptor/ion channel interactions repre-

sent the initial part of many signal pathways, key

enzymes which produce or inactivate second messen-

gers or amplify the signal can be important targets

further down the pathway (Table 6). These enzymes

include:

0024adenylyl cyclase (making cAMP),

0025phosphodiesterase (inactivating cAMP),

0026phospholipase (releasing arachidonic acid or

inositol phosphates) or

0027several protein kinases, such as protein kinase C

(which is activated by phorbol esters and the alkal-

oid chelerythrine) or tyrosine kinase (activating

other regulatory proteins or ion channels)

Because these targets are almost exclusively found

in animals but absent in plants, the development of

active compounds directed to these targets appears to

be advantageous for the plants producing them. They

can store these compounds without risk of being

intoxicated by their own toxins.

DNA/RNA

0028The genetic information of most organisms is mainly

encoded in DNA. Since the integrity of DNA is

important for the structure and function of rRNAs,

proteins and enzymes which are important for metab-

olism, structure and development of an organism,

DNA is a highly vulnerable target. It is not surprising

that a number of secondary metabolites became

selected during evolution which interact with DNA

or DNA-processing enzymes. Some alkaloids are

known to bind or to intercalate with DNA (Table 7).

Many of these molecules are planar, hydrophobic

molecules which fit between the planar stacks of AT

and GC base pairs. Other alkaloids act on the level of

DNA- and RNA-polymerases and DNA topoisomer-

ases, thus impairing the process of replication and

transcription.

0029The effects of DNA-binding or intercalating com-

pounds can be mutations, which may result in mal-

formations of newborn animals or in the initiation of

cancer. When anabasine, coniine, or anagyrine is ad-

ministered to pregnant cows or sheep, a large propor-

tion of the offspring develop malformations of the

tbl0006 Table 6 Alkaloids modulating enzymes involved in signal transduction

Enzyme Function Alkaloid Occurrence

Adenylyl cyclase cAMP formation Annonaine Annonaceae

b-carboline-1-propionic acid Leguminosae

Isoboldine Peumus

Tetrahydroberberine Berberidaceae

Phosphodiesterase cAMP inactivation Papaverine Papaver

Caffeine, theobromine Coffea,

Camellia,Theobroma

Theophylline Ilex paraguarensis,

Paulinia

1-ethyl-b-carboline Peganum

Protein kinases Protein phosphorylation Chelerythrine Chelidonium majus

Lyngbyatoxin A Marine seaweeds

cAMP, cyclic adenosine monophosphate.

tbl0005 Table 5 Alkaloids as modulators of Na

, and Ca

2þ

channels

Alkaloid Occurence (genera) Action

and K

channels

Aconitine

Aconitum Activation

Ajmaline

Rauwolfia Inhibition

Batrachotoxin

Frogs (Dendrobatidae) Activation

Harmalin Peganum Inhibition

Protoveratrine A, B

Veratrum Activation

Quinidine

Cinchona Inhibition

Quinine Cinchona Inhibition

Saxitoxin

Protogonyaulax (algae) Inhibition

Sparteine

Cytisus, Lupinus, Genista Inhibition

Tetrodotoxin

Algae/fish Inhibition

Veratridine

Veratrum Activation

2þ

channels

Ryanodine Ryania speciosa Inhibition

channel.

140 ALKALOIDS/Toxicology

legs – so-called ‘crooked calf disease.’ Some alkaloids

of the monocot Veratrum, such as jervine and cyclo-

pamine cause the formation of a large central eye, the

cyclopean eye, which was probably known to the

ancient Greeks and thus led to the mythical figure

of the cyclops.

0030 Other alkaloids are known as carcinogens, such as

aristolochic acid from Aristolochia and pyrrolizidine

alkaloids (PA) which are produced by approximately

3% of the higher plants, especially within the families

of Asteraceae and Boraginaceae. Aristolochic acid has

a nitro group which can be transformed into reactive

intermediates in the intestine. If resorbed, these me-

tabolites can alkylate DNA. Pyrrolizidine alkaloids

are not carcinogenic in their native form, but become

so when they are ‘detoxified’ in the liver: PA are

usually present in the plant as their N-oxides, which

are polar compounds that cannot pass biomembranes

by simple diffusion. In the intestine, PA-N-oxides are

reduced by gut bacteria. The free base is then readily

taken up by the gut cells and transported to the liver.

There, the PA are transformed into alkylating com-

pounds, which covalently bind to DNA and proteins.

As a result mutations and cancer can be initiated.

Protein Biosynthesis

0031 Protein biosynthesis is essential for all cells and

thus provides another important target. Indeed, a

number of alkaloids have been detected which

inhibit protein biosynthesis in vitro. Emetine from

Cephaelis ipecacuanha (Rubiaceae) is the most

potent plant constituent. Other alkaloids with the

same ability include harringtonine, homoharring-

tonine, cryptopleurine, tubulosine, hemanthamine,

lycorine, narciclasine, pretazettine, pseudolycorine,

tylocrepine, and tylopherine. Several alkaloids which

inhibit protein biosynthesis and are also DNA

intercalating substances can induce apoptosis in

cells.

Electron Chains and Other Enzyme Activities

0032The respiratory chain and ATP synthesis in mito-

chondria or photophosphorylation in chloroplasts

demand the controlled flux of electrons. These targets

seem to be attacked by nicotine, sanguinarine, ellipti-

cine, gramine, alpinigenine, capsaicine, and a few

other alkaloids. A multitude of enzymes exist in

animal cells and several alkaloids have been reported

that interfere with at least one of them.

0033A recently discovered group of alkaloids are the

polyhydroxyalkaloids, such as swainsonine or casta-

nospermine, which inhibit hydrolytic enzymes, such

as glucosidase, galactosidase, trehalase (trehalose

is a sugar found in some beetle cocoons and fungi

which is hydrolyzed by trehalase) and mannosidase

selectively.

tbl0007 Table 7 Alkaloids interacting with DNA/RNA and related enzymes

Target Activity Alkaloid Occurrence

DNA Photoaddition Dictamnine Dictamnus

Harman Peganum

Harmine Peganum

Alkylation Pyrrolizidine alkaloids Several Asteraceae, Boraginaceae

Aristolochic acid Aristolochia

Cycasin Cycads

Intercalation Ellipticine Ochrosia

Quinine, quinidine Cinchona

Skimmianine Skimmia

Berberine Berberis, Mahonia,Thalictrum, Chelidonium

Coptisine Several Papaveraceae

Fagaronine Rutaceae

Sanguinarine Several Papaveraceae

Olivacine Aspidosperma

Ergotamine Claviceps purpurea

Harmaline, harmin Peganum harmala

Emetine Cephaelis acuminata

DNA polymerase Inhibition Fagaronine Rutaceae

Hippeastrine Hippeastrum

Lycorine Several Amaryllidaceae

DNA topoisomerase I Inhibition Camptothecin Camptotheca acuminata

Reverse transcriptase Inhibition Berberine Several Berberidaceae, Papaveraceae

Chelidonine Chelidonium

RNA polymerase Inhibition Vincristine, vinblastine Catharanthus roseus

Transcription Inhibition Colchicine Colchicum, Gloriosa

amanitin Amanita

ALKALOIDS/Toxicology 141

Cytoskeleton

0034 Microtubules, which are important for cellular move-

ments, vesicle transport in neurons, or the separation

of chromosomes during cell division, are composed

of tubulin subunits. Movements and some transport

processes are mediated through either the rapid as-

sembly or disassembly of microtubules. The assembly

of microtubules is inhibited by colchicine, and

dimeric indole alkaloids vinblastine and vincristine

(important for chemotherapy of certain cancers).

These alkaloids thus interrupt cell division. The diter-

pene alkaloid taxol (used in the treatment of ovarian

and breast cancer) affects microtubules in the oppos-

ite way; the polymerization of tubulin is enhanced by

taxol. As a consequence taxol-induced microtubules

are very stable and dividing cells are arrested in the

metaphase.

0035 Cell stability, phagocytosis, cell–cell interactions,

and cell movements are also controlled by actin fila-

ments, which are rapidly assembled or disassembled

from action monomers. Cytochalasin B and latruncu-

lin B bind to the plus end of a growing actin filament,

preventing the addition of actin monomers there.

Another alkaloid, phalloidin, produced by the fatally

poisonous toadstool Amanita phalloides, stabilizes

actin filaments and inhibits their depolymerization.

Mechanisms of Allelochemical Activities

in Antiviral, Antimicrobial, and Phytotoxic

Interactions

0036 Circumstantial evidence indicates that some alkaloids

protect the producing plant against viruses, bacteria,

fungi, and competing plants. A number of antimicro-

bial alkaloids such as sanguinarine, quinine, or ber-

berine intercalate with viral and microbial DNA or

bind to it. These compounds may thus inhibit pro-

cesses such as DNA replication and RNA transcrip-

tion which are vital for the microorganisms. Protein

biosynthesis in ribosomes is another vulnerable target,

attacked by emetine. The stability of biomembranes

can be disturbed by steroidal alkaloids and tetran-

dine. Other targets may be electron chains or just

metabolically important enzymes. Phytotoxic proper-

ties or germination inhibition, which can be observed

in plant–plant interactions, can also proceed via the

above-mentioned mechanisms. But interactions with

growth hormones and their metabolism must also

be considered.

Target specificity of alkaloids

0037 In general, the interactions of a particular alkaloid

with a molecular target (as described above) suggest a

high degree of specificity. A closer look, however,

shows that many alkaloids interfere with more than

one target. The phenomenon will be explained for

two groups of alkaloids: ergot alkaloids and quinoli-

zide alkaloids (QA).

Ergot Alkaloids

0038Ergot alkaloids, such as ergotamine, ergometrine, or

ergoclavine, are produced by fungi of the genus Cla-

viceps which lives in close contact with many grasses

(family Poaceae) such as the cereal Hordeum vulgare.

These alkaloids can modulate several receptors of

neurotransmitters, such as dopamine, serotonin, and

norepinephrine. As a consequence. the pharmaco-

logical action of ergot alkaloids is rather broad,

ranging from vasoconstriction and uterus contraction

to hallucinations. We can explain these activities

through structure similarities between the alkaloid

and the different neurotransmitters.

Quinolizidine Alkaloids

0039QA, such as lupanine, sparteine, or cytisine, are pro-

duced by lupins and many members of the Legumi-

nosae. They are bitter for many animals (and plants

producing them are therefore avoided as food). If

ingested, QA exhibit a broad level of toxicity: they

interact with ACh receptors (AChR) as agonists. QA,

like many other alkaloids, occur as complex mixtures

in plants. Some QA preferentially bind to the nico-

tinic AChR, whereas others tend more to bind to the

muscarinic AChR. Some QA exhibit a prominent

cross-reactivity. Additionally, QA such as lupanine

and sparteine inhibit Na

and K

channels, thus

blocking the signal transduction in nerve cells at a

second critical point. A few particular QA, such as

anagyrine, cytisine, and the bipiperidine alkaloid

ammodendrine (which cooccurs with QA in many

plants), are mutagenic and lead to malformations

(see above).

0040If 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 com-

pound 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 allelo-

chemical. In addition, herbivores will try to develop

tolerance to or resistance against the dietary toxins.

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. In conclusion, 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. (See Trypsin

142 ALKALOIDS/Toxicology

Inhibitors; Saponins; Antibiotics and Drugs: Uses in

Food Production; Alkaloids: Properties and Deter-

mination.)

See also: Alkaloids: Properties and Determination;

Antibiotics and Drugs: Uses in Food Production;

Cereals: Dietary Importance; Coffee: Analysis of Coffee

Products; Lupin; Potatoes and Related Crops: The Root

Crop and its Uses; Plant Antinutritional Factors:

Characteristics; Saponins; Tea: Chemistry; Tomatoes;

Trypsin Inhibitors