1 Toxicology of alkaloids II. Toxic amines and aminoacids of plants Toxic plant proteins • Indolizidine alkaloids – Castanospermine • Castanospermum australe, Alexa leiopetala Fabaceae • Black bean tree • Inhibitor of α,β-glucosidase – Biogenesis glycoproteins • Inhibition of sugars utilization • Intoxication – Nausea, vomiting – Deadly for horses and cattle N OH OH OH OH H 2 – Swainsonine • Swainsonia, Astragalus, Oxytropis Fabaceae • Probably product of parasite – Fungus Rhizoctonia leguminicola • Damage of CNS – Axonopathy (locoism) – Inhibition of α-D-mannoxidase – Inhibition of biosynthesis of glycoproteins » Including hormones, membrane receptors, enzymes • Intoxication – Skeletar changes – Hepatosplenomegalia – Depression, exhaustion, nervosity – Tendention to aborts – Cardiovascular problems – Death from exhaustion of organism N OHOH OH H – Tylophorine, tylocrebine • Phenanthroindolizidine alkaloid • Tylophora spp., Asclepidiaceae • Ficus septica Moraceae • Skin irritant, vesicant compounds N O O O CH3 O CH3 CH3 CH3 3 • Tryptamines – Bufotenine • In water poorly soluble compounds • Piptadenia peregrina Mimosaceae – Cojoba Tree • Arundo donax Poaceae • Several fungi and frogs • Intoxication – Halucinogennic efect, influence on psychic » Similar to LSD and mescaline – Frame of mind: anxiety, percetion disorders – Mydriasis, hypertension – High dosage » Respiratory paralysis » Motoric paralysis – N,N-dimethyltryptamine (DMT) • Prestonia amazonica Apocynaceae • Piptadenia peregrina Mimosaceae • Shortly effective halucinogennic compound – 0,7-1mg/kg • Model psychosis – Vegetative symptomatology – Emocional and perception disorders – Illusions and visions – Space-time distortions NOH N CH3 CH3 4 5 – Physostigmine (eserine) • Physostigma venenosum Fabaceae • Competitive inhibitor of acetylcholinesterase • Administration i.v. highly toxic – Cca 1 mg • Symptoms of intoxication – Vomiting, colic, salivation – Diarrhea, sweating, vertigo – Bradycardia, miosis, total exhaustion – Respiratory paralysis CH3 N N CH3 CH3 O N O CH3 6 • β-carboline indol alkaloids • Harmane, harmaline, harmine • Peganum harmala, Zygophylum fabago, Tribulus terrestris Zygophyllaceae • Passiflora incarnata Passifloraceae • Inhibitory MAO – Elevated levels of neuromediators » Serotonine, noradrenaline – Especially in brain » Central effect – Early symptoms of intoxication » Nausea, vomiting, pale skin » Signs of aggression – Further progression » Half-sleep with dreaming » Hallucinations N CH3 N N N CH3 O CH3 N N CH3 O CH3 Peganum harmala 7 • Ergolines – Hlavně čeleď Convolvulaceae • Rivea corymbosa, Ipomoea spp. – Ergine (lysergamide) • Toxic dose 1 μg/kg p.o. • Mexican ceremonial drugs – Ololiuqui, coaxihuitl and further – Ergosine • Similarly to ergine • Inhibition of prolactine secretion – Chanoclavin – Agroclavine – Lysergol N N CH3 O NH2 H N O O N N O CH3 CH3 CH3 O N CH3 N H H N N CH3 CH3 OH H N N CH3CH3 H H N N CH3 OH H 8 • Monoterpenoid indols – Large group pf compounds – Biosynthesis from tryptophan and loganine – Apocynaceae, Loganiaceae, Rubiaceae – Huge spectrum of biologic activity and toxicity – Affinine, affinisine • Peschiera affinis, P. latea, Tabernaemontana psychotrifolia Apocynaceae • Toxic dose 300 mg/kg – Changes of behavior – CNS depression – Tremor, ataxia – Hypothermia, bradypnoe N O N OH H H Ajmalicine (raubasine) • Pausinystalia yohimbe, Rauwolfia spp., Vinca rosea Apocynaceae • Adrenolytic – Antagonist of α- receptors – Effect on vasomotoric centers in brain stem » Strong hypotensive 9 – Ajmaline • Rauwolfia spp. Apocynaceae • Inhibition of glucose utilization in myocardium • Toxic dosae – Convulsions, arrhythmia, strong fluctuation of blood pressure • Antagonist of thrombocyte activation • Agranulocytosis after long-termed use – Alstonine, serpentine • Rauwolfia spp., Vinca spp. Apocynaceae • Strychnos camptoneura Loganiaceae • Strong inhibitors of acetylcholine esterase • Negative chronotropic effect N OH N CH3 OH CH3 N N OO O H H N N OO O H H H –Brucine, strychnine • Strychnos spp. Loganiaceae • Toxicity –Stimulation of vasomotoric and respiratory centre » Block of inhibition aminoacid glycine –Spinal convulsant • Metabolism –Good gut absorption –Partially excreted unchanged via urine –Metabolism in liver • Intoxication –High sensitivity on sensoric stimuli –Convulsions » Generalized with agonizing pains » Respiratory and metabolic acidosis –Rapid onset of effect without warning » Anxiety, twitches of members and face, frightening image –Death caused by paralysis, total exhaustion, spastic paralysis of respiratory muscles, anoxia N N OO N N O O O O 10 – Gelsemicine, gelsemine, gelsemidine • Gelsemium sempervirens, Mostua spp. Loganiaceae • Highly toxic • Inhibitor of acetylcholinesterase • Toxicity – Respiratory depression – Tremor, discoordination of movements – Pralysis of numbsParalýza končetin – Urination, defacation, vomiting, salivation • Human – Vertigo, vision disorders, sweating – Muscle weakness, convulsions, respiratory depression O N O O N O H H 11 – Ibogaine, tabernathine • Tabernanthae iboga, Voacanga spp. Apocynaceae • Activity in CNS – Inhibitor of neronal nicotine receptors – Lower dosage » Central stimulation » Tremor, bristlin hair » Salivation, mydriasis » Anxiety, aggression – High doses » Hallucination serotonine effect » Deep depression and anxiety • Cardiovascular system – Negative ionotropic and chronotropic effect N N O H H N N O H 12 – Mitragynine • Mytragina speciosa, Unacana spp. Apocynaceae • Sedative effect on CNS, narcotic effect N N O O O O 13 –Reserpine •Rauwolfia spp. Apocynaceae •Toxicity –Depletion of CA a 5-HT in tissues »Inhibition of ATP-MG2+ mechanism of CA and 5-HT into neuronal vesicles •Intoxication –Pain in underbelly, diarrhea –Hypotension, depression, development of Parkinson syndrome •Chronic intoxication –Potential carcinogen, teratogen N N O O O O O O O O O H H H 14 – Schizozygine – Yohimbine • Mixture of α,β-isomers • Pausinystalia yohimbae, Corianthe spp., Pseudocinchona spp. Rubiaceae • Catharantus, Vinca, Ruwolfia Apocynaceae • Short-termed adrenolytic effect – Antagonist of α- adrenoreceptors » High selectivity for presynaptic α2adrenergic receptors • Antagonist of dopamine and serotonine • Symptoms of intoxication – Irritation, tremor, migraine, vertigo – Nausea, vomiting, diarrhea – Priapism N N OH O O H H H • Bis(indol) alkaloids – C-curarine, C- dihydroxytoxiferine • Calebas curare • i.v. toxicity – Calebasine • Strychnos spp. (S. divaricans, S. triervis…) Loganiaceae • South American calebas curare • Strong neuromuscular blockator • Deep long-termed loss of blood pressure • Complex muscular paralysis 15 – Toxiferine I (toxiferine C) • Strychnos spp. (S. divaricans, S. triervis…) Loganiaceae • South American calebas curare • Strong neuromuscular blockator 6-8× more effective than tubocurarine – Usambarensine, usambarine • Strychnos usambarensis Loganiaceae • African arrow poison • Muscular paralysis, antagonist of muscarine receptors N N N N H H 16 – Vinblastine, vincristine, leurosine, leurosidine • Vinca rosea, Apocynaceae • Inhibition of cell division – In metaphasis linkage to tubuline – Inhibition of mitotic spindle formation • Inhibition of synthesis of DNA and RNA • Toxicity – More toxic vincristine – Central and peripheral neurotoxicity » Parestesia, neuralgia, myalgia – Further effects » Alopecia, dyspnoe and bronchospasm » Headache, tramsient blidness » azoospermia – Teratogenic N N OH O O O O O N O O N OH H H N N O O OOO O O N O O N OH H H H • Other indol alkaloids – Mezembrenone, mezembrine, mezembrinol • phenyloxyindols • Sceletium alkaloids Aizoaceae • Narcotic, coca-like effect • Addictive drug – channa N O O O H Kosmatec 17 • Quinoline derivatives • Biogenetically derived from tryptophan or anthranilic acid • Not large number of compounds – Arborinine • Acridone alkaloid • Teclea spp. Rutaceae • Part of arrow poisons – Haplophylidine • Haplophyllum perforatum Rutaceae • Strong CNS depression N O OH O O O O O NOH O O –Quinine • Cinchona spp., Remija pedunculata Rubiaceae • Toxic dose 8-15 g • Protoplasmatic poison • Intoxication –GIT irritation » Vomiting, nausea –Neurologic symptoms » Diplopia, decreased perception of light » desorientation –Arrhytmia, hypotension –Oliguria, hematuria –Spermatocidal, induction of abortus or premature birth N OH N O H 18 – Calycanthine • Calycanthus spp., Chionantus spp. Calycanthaceae • Palicourea alpina Apocynaceae • Toxicity – Convulsions, cardiac depression, paralysis – Stimulation of uterus NN N N – Campthotecine • Camptotheca acuminata Nyssaceae • Gastrointestin toxicity – vomiting, nausea and diarrhea • myelosupression, hemorrhagic cystitis, dermatitis • Important cytotoxicicty – Inhibition of topoisomerase I » Formation of covalent bonds • Topotecane, irinotecane O O O N O N 19 • Imidazol derivatives – Small group of compounds derived from histidine – Alchorneine, alchornine • Alchornea floribunda, A. hirtela Euphorbiaceae • iporuru N N O 20 – Pilocarpine, pilosine • Pilocarpus spp. Rutaceae • Cholinergic activity – Salivation, lachrymation – Increased stomach secretion – Increased gut motility – Bronchial constriction – Excitation to epileptic state O O N N • Diterpenic alkaloids – Biologic precursor isoprene • Consequent introduction of nitrogen – Pseudoalkaloids – Aconitum spp., Consolida spp., Delphinium spp Helleboraceae – Ester alkaloids more toxic – Non-ester so called atisine alkaloids less toxic – Aconitine • Diterpenic ester compound • Aconitum spp. Helleboraceae • Toxic dose 3-6 mg p.o. (2-15 g of tubers) • Cardiotoxicity, neurotoxicity • Rapid absorption – Good transition through membrane – Absorption through the skin • Persistant opening of sodium channel of axones • Inhibition of repolarisation • Symptoma of intoxication – Anaesthesia of tongue – Nausea, vomiting – Diarrhea, colic – Parestesia » „pins and needles“, chills » pains – Mydriasis changes to miosis – Arrhytmia, paralysis – Death » Ventricular fibrilation » Respiratory arrest N O O OH O O O OH OH O O O H H H 21 – Taxin A • Pseudoalkaloid • Taxus baccata Taxaceae • Main alkaloid of yew • Cattle intoxication from eating of needles • Suicides – 50-100 g of needles for adult man • Symptoms – After 30 minutes – Nausea, vomiting – Vertigo – Painful stomach colic – Shallow respiration, arrhythmias » Similar to hypokalemia – Death » Respiratory paralysis » Cardiac arrest in diastole OH O O O OH O O O O OH N • Steroid alkaloids – C-21 alkaloids of pregnane type • Apocynaceae and Buxaceae – C-24 alkaloidy derived from cycloartenol • Buxaceae – C-27 alkaloids • Solanaceae and Liliaceae – Alkaloids Solanaceae • Derivatives of solanine and spirosolane • In form of glycosides • Physico-chemical properties similar to saponins • Inhibitors of acetylcholinesterase • Formation of GIT necrosis – Alkaloids Liliaceae • Heterocyclus of different viosynthetic origin • C-nor-D-homosteroids • Effect on heart similar to cardioglycosides • Effect on blood pressure • Veratrum spp. – teratogenic 22 – Buxamine, Cyclobuxine A, B, C, D • Buxus spp. Buxaceae • Convulsants • Vomiting, colics of GIT • Diarrhea, muscular pain – Cyclopamine, cycloposine • Veratrum spp. Liliaceae • Strong teratogen – Malformation of cyclopia type • Dual mechanism: 1. Interference with development of vývojem embrional tube – Hit into function of neuroembryonal epithel » Inhibition of catecholamine release – Craniofacial deformation 2. Interference with metabolism ofcartilages – Tracheal stenosis – Contraction of metacarpal and metatarsal bones – Contraction of tibias – Jervine • Veratrum spp. Liliaceae • 1g acute toxicity • Teratogen • Circulatory failure, diarrhea, convulsions O N OH N N O N O OH H H H H H 23 – Germine, germidine • Zygadenus venenosum, Veratrum spp. Liliaceae • Strong emetics • Cardiotoxic compounds – Arrhythmias, slowering of excitement transition – Protoveratrine A and B • Veratrum spp. Liliaceae • Lethal dose 20 mg • Symptoms of intoxication – Inflammation of oral mucosa – Anesthesia of mucosa membrane – Vomiting, diarrhea – Sneezing, nasal bleeding, lachrymation, congestion of conjuctiva – Dilatation of vessels (influencing baroreceptors) » Lowering of blood pressure, bradycardia, bradypnoe • Death – Cardiac and respiratory failure O OH OH OH OH OH OH N OH H H H H H H O OH O OH O O O OH O N O O OH O OH H H H H H H 24 – α-solanine, α-chakonine • Glycosylated form more toxic than aglycon solanidine • Solanum spp. Solanaceae • Presence of alkaloids in whole plant • In tubers variable content – Increased by different factors » Genetic, rippening, fertilization » Mechanic damage, stressors • Heat resistance, only removal by hot water • High glycoalkaloids content – Burning and bitter taste • Low absorption from GIT – advantage, safe – Intoxication at more than 1 mg/kg • Mechanism of intoxication – Inhibitors of acetylcholinesterase – Damage of mucose layer of GIT » Necrosis, gastroenteritis • Symptoms – Nausea, vomiting, diarrhea – Stomach pain, headache, vertigo – Halucination, neurologic disorders, coma N OO O O O O O O O O O O O O O H H H H H H 25 • Chinazolinové alkaloidy – Vasicine, vasicinol, vasicinone • Adhatoda vasica Acanthaceae • Lunaria spp. Brassicaceae • Peganum harmala Zygophyllaceae • Stimulation of uterus – Probably via deliberation of prostaglandins • Abortive effect • Fast absorption, upto 30 minut max. concentration in target tissue N N OH • Securinega alkaloids – Sekurinin, virosekurinine, norsecurinine • Nitrogenous tricycle with butenolide ring – Typical for cardioglycosides • Securinega suffruticosa, Phyllanthus discoides Euphorbiaceae • Stimulation effect on CNS (spinal cord) • Affection of autonomous nerve system • Antagonists at GABA receptor • Toxic doses 5-10 mg/kg – Stimulation similarly to strychnine – Convulsions, death via espiratory failure • i.v. and p.o. administration – Extremly fast onset, but rapid metabolism • High cytotoxicity O N O H 26 Toxic aminoacids and amines • Aminoacids • Production of more than 300 non-protein AMA • Free or as γ-glutamylpeptids • Metabolic interaction in strange organism – Similarity to protein AMA • toxicity – Direct antagonists • Lowering of intake of AMA through membranes • Block of implementation of AMA into protein • Problem especially for young and developing organism • For fetus - teratogenic – Indirect antagonists • Inhibition of oxidation of faty acids – Organism switches metabolism to saccharides utilization » Deadly hypoglycaemia • Strumigens • Metabolism of selenium – selenosis • Protein AMA – In supraphysiological concentration • Neurotoxins (glutamate, aspartate) – GABA • Seeds of Fabaceae, Pisum, Vicia, Phaseolus • Inhibition neurotransmitter – L-α-amino-γ-oxalylaminobutyric acid • Lathyrus, Acacia Fabaceae • Osteolathyrism – Inhibitor of aminooxidase to convert lysyl to lysylaldehyde » Malfunction of collagen networking » Loss of cohezion between cartilage and epiphysis of bone • Neurolathyrism » Neurotoxic syndrome » Mediterranean, India, Asia Minor » Lowered tonus of muscles, consequent paralysis – L-α-amino-β-oxalylaminopropionic acid • Lathyrus, Crotolaria Fabaceae • Similar to above mentioned, can cause chronic disorders and death • Neurolathyrismus – Inhibition of liver aminotrasferase » Increased levels of tyrosine » Increased synthesis of DOPA, dopamine and toxic metabolites 27 28 – β-aminopropionilnitrile • Lathyrus spp. Fabaceae • Osteolathyrism – Asparagic acid • Protein AMA – ubiquitous • Toxicologic important high levels in Centaurea solstitialis Asteraceae • Extrapyramidal disease – Nigropallidal encephalomalacia – Animals on pasture, mainly horses – Excitation neurotransmitter – Brain damage – Manifestation during feeding and drinking - chewing desease – Animals with low mobility, to spontaneous physical activity – Similar to glutamate – L-djenkolic acid • Albizia lophanta, Acacia spp., Mimosa spp. Mimosaceae • Djenkol bean ,velvet bean – Vegetable of SouthEast Asia • Long-termed intake – Formation of needleshaped crystals in kidneys – Mechanic damage of kidney parenchyma 29 – Hypoglycine B and A • Unripen seeds and fruits of Blighia sapida Sapindaceae • Seeds of maples Acer spp. • Mechanism of toxicity – Inhibition of Cori cycle – Inhibition of glucose/glukose-6phosphate cycle – Inhibition of oxidation of fatty acids – Inhibition of gluconeogenesis • Symptoms – Deep hypoglycemia – Vomiting » Formation of isovaleric acid via inhibition of leucine metabolism – Total degradation of liver glycogen – Accumulation of fat in liver • Death via general failure • Common intoxications – L-canavanine • Seeds of different Fabaceae • Analogue of arginine – Arginyl-RNA synthase uses it – Incorporation to peptides » Non-functional » Interference with synthesis of RNA/DNA and proteins – Interferrence with arginine metabolism – Inhibition of NO-syntethase – Increased production of superoxide radical • Toxicity – Teratogen – Evocation of aborts – Hepatotoxic 30 – Se-methyl-L-selenocysteine – L-selenocystathionine • Seeds of Fabaceae plants Astragalus spp. Melilotus spp. • Brassicaceae • Growth on soils with high selenium content • High intake of selenium toxic mainly for animals – selenosis • Incorporation of selenium instead of sulphur into AMA • Disruption of protein synthesis • Inhibition of selenium detoxication – methylation – hepatotocity • Amines – Ephedrine • Aromatic amine • Ephedra spp. Ephedraceae • Sympathomimetic activity – Increase of blood pressure and peripheral vasoconstriction – Penetration to CNS • Acute intoxication – Sweating, headache, anxiety – Muscular weakness and tremor – Mydriasis – Palpitation – Insomnia – Galegine • Galega officinalis Fabaceae • Derivative of guanidine • Damage of mitochondrial function • Convulsions, breath difficulties, pulmonary edema 31 – Khatamines • Arylalkylamines • Catha edulis, Maytenus crucorii Celestraceae • Ephedra spp. Ephedraceae • Khatine and khatinone the most important • Khatinone – Similar properties to amphetamine – During drying converts to norpseudoephedrine and norephedrine • Drug is used via chewing – North-East Africa – Fast decomposition prevents large transportation and business – Suppression of sleep, stimulation, against fatigue • Intoxication – Anorexia, hyperthermia, stimulation of respiratory centre – Mydriasis, arrhythmia, hypertension – Psychic symptoms » Anxiety, panic attack, aggresivity 32 • Toxic proteins – Lectins (phytohemaglutinines) • Proteins or glycoproteins containing 4-10 % of sugar component • Molecules from 4 subunits – Connection via non-covalent bonding • Ability to bind the sugar residues on the surface of cell – D-galactose, N-acetyl-D-galactosamine – More binding sites » Ability to li up neighboring cells - agglutination • Inhibition of protein synthesis of eukaryota • Some lectins – Inhibition of mitosis – Stimulation of lymphocyte maturation – Killing of cancer cells • Toxicity – Binding to cells of GIT mucosa membrane » Inhibition of absorption of nutrients – antinutrition factors » Vomiting, hemorrhagic diarrhea, loss of water and electrolytes • Occurrence in plants – Seeds and fruits of Fabaceae, Brassicaceae, Ericaceae • Content in plants different – Influenced by heat treatment • Abrine – Abrus precatorius, A. pulchelus Fabaceae – Mixture of similar compounds abrine-a and abrine-b » Each chains A and B » Connection via disulphide bridges – A inhibition of proteosynthesis » Cell death – B binding to a membrane of GIT cell, enables the entry of A into cell – LD for mice p.o. 25 μg, highly toxic compounds – Intoxication » Hemorrhagic diarrhea » Electrolyte dysbalance » Arrhythmia, brain edema » Convulsions, cardiovascular collapse » Death 33 • Phasine – Phaselolus vulgaris Fabaceae – Mixture of five isolectines – High p.o. toxicity – Linkage to cells of GIT epithelium, partially pass into blood circulation » Detoxication in liver or kidneys » Non-metabolized part - slowering of growth - interruption of hormones synthesis - decrease of production of muscle proteins – Hypertrophy of intestine – Hypertrophy of liver and pancreas • Ricine D – Ricinus communis Euphorbiaceae – Component of ricine – 4 lectines » RCLI and RCLII non-toxic » Ricine D and RCLIV toxic – Dimeric » Chains A and B connected by disulphide » B enables linkage to cell » A is a cytotoxin – High toxicity » 1 mg in 1 g of seeds is a lethal dose – Interference with protein synthesis and inactivation of ribosomal subunit 28S – Very sensitive are glial cells – Oral intoxication – ricinism » Nausea, headache » Bloody diarrhea, dehydratation » EKG changes » Liver necrosis » Coma, death 34 • Viscolectins – Viscum album Viscaceae – ML I, ML II (viskumin) a ML III – Specific to D-galactose (ML I) – Specific to N-acetyl-Dglucosamine (ML III) – Specific binding to both these sugars (ML II) – Inhibition of proteosynthesis by inactivation of 60S subunit – Damage of cell membrane – Toxic for a panel of animal species • Viscotoxins – Viscum album, Phoradendron Loranthaceae – Specific proteins – Resistant to proteases and increased temperature – Toxic for myocardium – Inhibition of DNA synthesis – Damage to hepatocytes similar to damage caused by hepB – Acute intoxication » Vomiting, stomach convulsions, diarrhea » Cardiac collapse