Tutin (toxin)

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Tutin
Tutin.svg
Clinical data
ATC code
  • none
Identifiers
  • (1S,2R,3S,5R,6R,7R,8S,9R,12R)-2,8-dihydroxy-7-methyl-12-prop-1-en-2-ylspiro[4,10-dioxatetracyclo[7.2.1.02,7.03,5]dodecane-6,2'-oxirane]-11-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard 100.236.780 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H18O6
Molar mass 294.303 g·mol−1
3D model (JSmol)
  • CC(=C)[C@@H]1[C@@H]2[C@H]([C@]3([C@@]4(CO4)[C@H]5[C@@H]([C@]3([C@H]1C(=O)O2)O)O5)C)O
  • InChI=1S/C15H18O6/c1-5(2)6-7-12(17)20-8(6)9(16)13(3)14(4-19-14)10-11(21-10)15(7,13)18/h6-11,16,18H,1,4H2,2-3H3/t6-,7+,8+,9+,10+,11-,13-,14+,15-/m0/s1
  • Key:CCAZWUJBLXKBAY-ULZPOIKGSA-N
   (verify)

Tutin is a poisonous plant derivative found in New Zealand tutu plants (several species in the genus Coriaria ). It acts as a potent antagonist of the glycine receptor, [1] and has powerful convulsant effects. [2] It is used in scientific research into the glycine receptor. It is sometimes associated with outbreaks of toxic honey poisoning when bees feed on honeydew exudate from the sap-sucking passion vine hopper (Scolypopa australis) insect, when the vine hoppers have been feeding on the sap of tutu bushes. Toxic honey is a rare event and is more likely to occur when comb honey is eaten directly from a hive that has been harvesting honeydew from passionvine hoppers feeding on tutu plants. [3]

Contents

History

Tutin was first discovered as a honey contaminant in the late 19th century. Missionaries from overseas introduced the western honey bee (Apis mellifera) to New Zealand in 1839. A few decades later, people eating the local honey would suffer from symptoms like vomiting, headaches and confusion. [4] At this point the neurotoxin was studied, and in the early 1900s its toxic effects were fully characterised. [4] The toxin was known to come from the tutu plant. However, neither the nectar nor the pollen of the tutu plant contain this toxin, the two parts the honey bees ingest. Eventually it was found that the passion vine hopper (Scolypopa australis), a pest insect, extracts sap from young shoots of the tutu plant and releases secretions, honeydew, that contain the tutin toxin. [4] Honeybees will consume honeydew as a supplementary food source, thereby contaminating the honey they produce with this toxin. [4] Further outbreaks of tutin poisoning would periodically appear from that point onwards. As late as 2008 a family had to be hospitalized due to severe symptoms caused by homegrown honey with tutin contaminations. [4]

Structure and chemical properties

Tutin is a polyoxygenanted polycyclic sesquiterpene from the picrotoxane family. [5] Tutin is one of a series of chemically and pharmacologically similar compounds of which picrotoxinin [6] and coriamyrtin [7] have been mostly studied. Conroy [8] [9] proposed the structure for picrotoxinin, which was confirmed by X-ray crystallographic studies and also determined the absolute configuration of the molecule. [10] [11] Karyone and Okuda proposed the tutin [12] structure based on the pictrotoxinin structure and chemical degradation studies. The structure of tutin including absolute stereochemistry was confirmed by X-ray crystal analysis [5] [13] together with chemical and chiroptical means. [14] [15] Tutin has a highly strained skeleton, including two epoxide rings and a lactone, which is susceptible to various rearrangements. Tutin has a characteristic intensely bitter taste. Tutin is very soluble in acetone, but dissolves moderately in chloroform and is insoluble in carbon disulfide or benzene. Addition of strong sulfuric acid to a few drops of a saturated aqueous solution of tutin results in a blood-red coloration. [16]

Isolation from nature

In 1901, tutin was first isolated by Easterfield and Aston and identified as the convulsive poison present in the New Zealand species of Coriaria (‘’tutu’’ or ‘’toitoi’’ in Maori). Easterfield and Aston used 1.5 kilograms of seeds and 11 kilograms of the air-dried Coriaria thymifolia plant (without roots) from Dunedin at the time of flowering in January. The seeds were pulverised and exhausted by carbon disulfide removing a green drying oil. The plant was put through a chaff cutter and boiled with water. The mixture was treated with a large volume of ethanol. The ethanol precipitated inorganic salts, ellagic acid and a large amount of black matter. After distilling, the residue was extracted with diethyl ether. The crystals were recrystallized several times from water, which resulted in separating of the substance in characteristic needle forms and recrystallization from ethanol in oblique ended prisms. The final product contained the characteristic highly poisonous non-nitrogenous glucoside[ clarification needed ] tutin as colourless crystals melting at 204–205 °C (399–401 °F). [16]

Chemical synthesis of (+)-tutin

In 1989, Wakamatsu and coworkers reported in details the first total synthesis of (+)-tutin in a stereocontrolled manner. (+)-Tutin can be synthesized in a nine-step reaction process. First, a (-)-bromo alcohol was protected by silylation. After this step, conversion of the allylic bromide moiety into the allylic alcohol was achieved by the Corey's conditions. [9] Next, the hydroxyl moiety was introduced at C-2, regio- and stereoselectively of the intramolecular reaction was due to the use of the C-14 hydroxyl function to gain the desired cyclic ether. Thereafter, the ethereal bond was cleaved providing the allylic bromide. Subsequently, the silyl protection group was removed by using tetra-n-butylammonium fluoride in THF. The intramolecular SN2 reaction at the allylic bromide moiety led to the formation of the epoxy olefin. Then, the epoxy olefin was converted into the bisepoxide in three-steps, first alkaline hydrolysis to give the alcohol, second esterification to form 2,2,2-trichloroethyl carbonate and as last epoxidation. Thereafter, the bisepoxide was oxidized with ruthenium(VII)oxide affording 2,2,2-trichloroethoxycarbonyl α-bromotutin. The final part of the synthesis of (+)-tutin is a reduction with zinc and ammoniumchloride. [17]

Chemical reactions

Acylation of the secondary alcohol 2-OH [18] and double acetylation at both the 2-OH and C6-OH [19] of tutin has been reported. In the New Zealand toxin honey two main structures of tutin conjugates were found; 2-(β-D-glucopyranosyl)-tutin and 2-[6’-(α-D-glucopyranosyl)-β-D-glucopyranosyl]-Tutin. [20] Chemical synthesis of 2-(β-D-glucopyranosyl)-tutin could be achieved via the β-O-glycosylation reaction between tutin and an activated sugar donor. [4] Multiple methods of O-glycosylation have been published about the synthesis of complex glycosides with anomeric β-stereoselectivity. [21]

Mechanism of action

GABA (γ-aminobutyric acid) is a major inhibitory neurotransmitter in the central nervous system of mammals. Tutin is an antagonist of the GABA receptors. By inhibiting these receptors, the sedative effect of this neurotransmitter is lessened, leading to intensive stimulation of the nervous system. Based on extensive data, tutin was determined to be a non-competitive antagonist [22] using an allosteric mechanism. [23]

Apart from GABA receptor inhibition, in vitro studies have also shown tutin to have an inhibitory effect on the glycine receptors of the neurons in the spinal cord. These receptors have inhibitory functions comparable to those of the GABA receptors. [1]

Lastly, investigation into similar toxins has shown them to be blockers for other ligand-gated ion channels. Therefore, it is suspected that tutin could also possess antagonistic properties against other ion channels. [24]

Metabolism

Laboratory animal studies on the absorption, distribution, metabolism and excretion of tutin are not available. According to Fitchett and Malcolm 1909, [18] McNaughton and Goodwin 2008, [25] the systemic absorption of purified tutin after an oral ingestion appears rapid in animals as clinical signs that are consistent with neurotoxicity where found to appear within less than 15 minutes in mice and after about one hour in dogs. Animals that received non-lethal doses showed a rapid recovery suggesting a fast elimination. [25] Onset time of toxicity following the consumption of tutin containing honey is on the contrary highly variable. In 2008, a median onset time of 7.5 hours was found for the 11 confirmed cases with onset times ranging from half an hour to 17 hours after ingestion. [4]

Biological effects

Tutin has a toxic effect on both mammals and insects. It was looked into whether or not it would make a useful rodenticide. In rats it had a lethal effect within one hour at a dose rate of 55 mg/kg body weight. However, it was recommended that a more specific toxin should be used. [21]

In humans it also has a toxic effect. Although the exact doses remain unknown, people have been incapacitated, hospitalised or even died from getting tutin into their system. A study has been conducted in which six men were given a tutin dose of 1.8 μg/kg body weight. Although the effects were hardly felt by the volunteers, unusual serum concentrations were observed. A peak in tutin concentration was observed one hour after ingestion, and a second, larger and prolonged peak was observed around 15 hours after ingestion. The reasons for this observation have yet to be determined. [26] Side effects of tutin intoxication include: headaches, nausea, vomiting, dizziness and seizures. [26]

The biological activities of tutin have been reported to be nearly identical with those of the other picrotoxane sesquiterpenes; picrotoxinin and coriamyrtin. [27] Symptoms of tutin poisoning are for example: preliminary depression, salivation, a fall in the frequency of the pulse, increased breathing, and convulsions. The effect is due to an action on the medulla oblongata and basal ganglia of the brain. [16]

Toxicity

The effects of tutin poisoning were described to be salivation, a diminished heart beat, increased respiratory activity and later, predominantly clinic seizures which are in their early stages limited to the fore part of the body. [16] Results of published acute toxicity studies on various animals are of limited value because of the uncertainty in the impurity profile for the administered tutin. For instance, Palmer-Jones (1947) [28] reported an LD50 of 20 mg/kg of tutin via oral administration in rats. Administration via subcutaneous (SC) and intraperitoneal (IP) routes showed a higher acute toxicity with LD50 of approximately 4 and 5 mg/kg. [3] Little is known about the lethal dose in the average human though tests have been performed on various animal species. For instance, intraperitoneal injection of tutin in rats has shown that concentrations of 3, 5 and 8 mg/kg were lethal whilst 1 mg/kg was non-lethal with all rats showing symptoms such as muscle spasms and general seizures. [1] Documented human exposure to tutin implied that a dose of about a milligram causes nausea and vomiting in a healthy, full grown man. [16]

Effects on animals

Tutin has been known to cause death in sheep and cattle belonging to the settlers of New Zealand. Therefore, extensive research on the effects of tutin on different animal species has been done in the early 20th century. The symptoms after injection were more or less the same in all animals, and included rapid breathing, salivation, seizures and eventually death. The minimal lethal dose in cats and dogs was found to be around 1 mg/kg. In small rodents like rats, rabbits and guinea pigs, the minimal lethal dose was a little higher, around 2.5 mg/kg. In young animals, the minimal lethal dose is lower. Birds were thought to be immune to tutin poisoning, because they feed on the berries of the turin plant. After research it became clear that birds have a high minimal lethal dose (around 10.25 mg/kg), but no absolute immunity. The apparent immunity in natural circumstances is because in order to reach a dose of 10.25 mg/kg, the birds need to eat more of the berries than they physically can. [18] The relatively high lethal dose can be explained by the way birds digest food. From the crop (a part of the throat in many birds where food is stored before going into the stomach), the veins go directly to the systemic circulation, instead of first through the liver like in mammals.[ clarification needed ]

Related Research Articles

In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose required to kill half the members of a tested population after a specified test duration. LD50 figures are frequently used as a general indicator of a substance's acute toxicity. A lower LD50 is indicative of higher toxicity.

<span class="mw-page-title-main">Toxin</span> Naturally occurring organic poison

A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. They occur especially as proteins, often conjugated. The term was first used by organic chemist Ludwig Brieger (1849–1919) and is derived from the word "toxic".

<span class="mw-page-title-main">Aconitine</span> Toxic plant alkaloid

Aconitine is an alkaloid toxin produced by various plant species belonging to the genus Aconitum, known also commonly by the names wolfsbane and monkshood. Monkshood is notorious for its toxic properties.

<span class="mw-page-title-main">Thujone</span> Group of four possible stereoisomers found in various plants: a.o., absinthe and mint

Thujone is a ketone and a monoterpene that occurs predominantly in two diastereomeric (epimeric) forms: (−)-α-thujone and (+)-β-thujone.

<span class="mw-page-title-main">Strychnine</span> Poisonous substance used as pesticide

Strychnine is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eyes or mouth, causes poisoning which results in muscular convulsions and eventually death through asphyxia. While it is no longer used medicinally, it was used historically in small doses to strengthen muscle contractions, such as a heart and bowel stimulant and performance-enhancing drug. The most common source is from the seeds of the Strychnos nux-vomica tree.

<span class="mw-page-title-main">Saxitoxin</span> Paralytic shellfish toxin

Saxitoxin (STX) is a potent neurotoxin and the best-known paralytic shellfish toxin (PST). Ingestion of saxitoxin by humans, usually by consumption of shellfish contaminated by toxic algal blooms, is responsible for the illness known as paralytic shellfish poisoning (PSP).

<span class="mw-page-title-main">Palytoxin</span> Chemical compound

Palytoxin, PTX or PLTX is an intense vasoconstrictor, and is considered to be one of the most poisonous non-protein substances known, second only to maitotoxin in terms of toxicity in mice.

<span class="mw-page-title-main">Tutu (plant)</span> New Zealand plants in the genus Coriaria

Tutu is a common name of Māori origin for plants in the genus Coriaria found in New Zealand.

<span class="mw-page-title-main">Epibatidine</span> Toxic chemical from some poison dart frogs

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

<span class="mw-page-title-main">Cicutoxin</span> Chemical compound

Cicutoxin is a naturally-occurring poisonous chemical compound produced by several plants from the family Apiaceae including water hemlock (Cicuta species) and water dropwort (Oenanthe crocata). The compound contains polyene, polyyne, and alcohol functional groups and is a structural isomer of oenanthotoxin, also found in water dropwort. Both of these belong to the C17-polyacetylenes chemical class.

<span class="mw-page-title-main">Orellanine</span> Chemical compound

Orellanine or orellanin is a mycotoxin found in a group of mushrooms known as the Orellani of the family Cortinariaceae. Structurally, it is a bipyridine N-oxide compound somewhat related to the herbicide diquat.

<span class="mw-page-title-main">Lupinine</span> Chemical compound

Lupinine is a quinolizidine alkaloid present in the genus Lupinus of the flowering plant family Fabaceae. The scientific literature contains many reports on the isolation and synthesis of this compound as well as a vast number of studies on its biosynthesis from its natural precursor, lysine. Studies have shown that lupinine hydrochloride is a mildly toxic acetylcholinesterase inhibitor and that lupinine has an inhibitory effect on acetylcholine receptors. The characteristically bitter taste of lupin beans, which come from the seeds of Lupinus plants, is attributable to the quinolizidine alkaloids which they contain, rendering them unsuitable for human and animal consumption unless handled properly. However, because lupin beans have potential nutritional value due to their high protein content, efforts have been made to reduce their alkaloid content through the development of "sweet" varieties of Lupinus.

<span class="mw-page-title-main">Methyllycaconitine</span> Chemical compound

Methyllycaconitine (MLA) is a diterpenoid alkaloid found in many species of Delphinium (larkspurs). In common with many other diterpenoid alkaloids, it is toxic to animals, although the acute toxicity varies with species. Early research was focused on identifying, and characterizing the properties of methyllycaconitine as one of the principal toxins in larkspurs responsible for livestock poisoning in the mountain rangelands of North America. Methyllycaconitine has been explored as a possible therapeutic agent for the treatment of spastic paralysis, and it has been shown to have insecticidal properties. Most recently, it has become an important molecular probe for studying the pharmacology of the nicotinic acetylcholine receptor.

Persin is a fungicidal toxin present in the avocado. Persin is an oil-soluble compound structurally similar to a fatty acid, a colourless oil, and it leaches into the body of the fruit from the seeds.

<span class="mw-page-title-main">Bees and toxic chemicals</span>

Bees can suffer serious effects from toxic chemicals in their environments. These include various synthetic chemicals, particularly insecticides, as well as a variety of naturally occurring chemicals from plants, such as ethanol resulting from the fermentation of organic materials. Bee intoxication can result from exposure to ethanol from fermented nectar, ripe fruits, and manmade and natural chemicals in the environment.

<span class="mw-page-title-main">Anisatin</span> Chemical compound

Anisatin is an extremely toxic, insecticidally active component of the shikimi plant. The lethal dose is 1 mg/kg (i.p.) in mice. Symptoms begin to appear about 1–6 hours after ingestion, beginning with gastrointestinal ailments, such as diarrhea, vomiting, and stomach pain, followed by nervous system excitation, seizures, loss of consciousness, and respiratory paralysis, which is the ultimate cause of death.

<span class="mw-page-title-main">Surugatoxin</span> Chemical compound

Surugatoxin (SGTX) is a type of venom found in the mid-gut digestive gland of the Japanese ivory mollusk Babyloniajaponica, a carnivorous gastropod. It functions as a ganglionic blocker of nicotinic acetylcholine receptors (nAChRs). The structurally and functionally related neosurugatoxin, also derived from Babylonia japonica, is an even more potent nAChR antagonist than SGTX.

<i>Coriaria arborea</i> Species of plant

Coriaria arborea is a highly poisonous and common native shrub or small tree of New Zealand. The common name for this and the other New Zealand species of Coriaria is tutu.

<span class="mw-page-title-main">Gelsemine</span> Chemical compound

Gelsemine (C20H22N2O2) is an indole alkaloid isolated from flowering plants of the genus Gelsemium, a plant native to the subtropical and tropical Americas, and southeast Asia, and is a highly toxic compound that acts as a paralytic, exposure to which can result in death. It has generally potent activity as an agonist of the mammalian glycine receptor, the activation of which leads to an inhibitory postsynaptic potential in neurons following chloride ion influx, and systemically, to muscle relaxation of varying intensity and deleterious effect. Despite its danger and toxicity, recent pharmacological research has suggested that the biological activities of this compound may offer opportunities for developing treatments related to xenobiotic or diet-induced oxidative stress, and of anxiety and other conditions, with ongoing research including attempts to identify safer derivatives and analogs to make use of gelsemine's beneficial effects.

<span class="mw-page-title-main">Atractyloside</span> Chemical compound

Atractyloside (ATR) is a natural, toxic glycoside present in numerous plant species worldwide in the daisy family including Atractylis gummifera and Callilepis laureola, and it's used for a variety of therapeutic, religious, and toxic purposes. Exposure to ATR via ingestion or physical contact is toxic and can be fatal for both humans and animals, especially by kidney and liver failure. ATR acts as an effective ADP/ATP translocase inhibitor which eventually halts ADP and ATP exchange and the cell dies due to lack of energy. Historically, atractyloside poisoning has been challenging to verify and quantify toxicologically, though recent literature has described such methods within acceptable standards of forensic science.

References

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  2. ↑ Zhou H, Tang YH, Zheng Y (May 2006). "A new rat model of acute seizures induced by tutin". Brain Research. 1092 (1): 207–213. doi:10.1016/j.brainres.2006.03.081. PMID   16674929. S2CID   23612567.
  3. 1 2 Animal Products Group (October 2003). "Background on toxic honey". New Zealand Food Safety Authority. Archived from the original on 4 January 2007.
  4. 1 2 3 4 5 6 7 Ghosh D (August 2014). "Food safety regulations in Australia and New Zealand Food Standards". Journal of the Science of Food and Agriculture. 94 (10): 1970–1973. Bibcode:2014JSFA...94.1970G. doi:10.1002/jsfa.6657. PMID   24638225.
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  6. ↑ Sutter M, Schlittler E (1949-10-15). "Pikrotoxin 3. Mitteilung. Sodaspaltung von ?-Dihydro-pikrotoxinin". Helvetica Chimica Acta. 32 (6): 1855–1860. doi:10.1002/hlca.19490320607. ISSN   0018-019X.
  7. ↑ Sugita H (1985). "Sobolev spaces of Wiener functionals and Malliavin's calculus". Journal of Mathematics of Kyoto University. 25 (1): 31–48. doi: 10.1215/kjm/1250521157 . ISSN   0023-608X.
  8. ↑ Conroy H (April 1951). "The Skeleton of Picrotoxinin". Journal of the American Chemical Society. 73 (4): 1889. doi:10.1021/ja01148a551. ISSN   0002-7863.
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  10. ↑ Craven BM (January 1960). "The molecular structure and absolute configuration of picrotoxinin". Tetrahedron Letters. 1 (40): 21–24. doi:10.1016/s0040-4039(01)99349-9. ISSN   0040-4039.
  11. ↑ Craven BM (1959-03-10). "The crystal data for the chloro and bromo derivatives of picrotoxinin". Acta Crystallographica. 12 (3): 254. doi: 10.1107/s0365110x59000755 . ISSN   0365-110X.
  12. ↑ "Table of Contents, Publ. Res. Inst. Math. Sci., Kyoto Univ., Ser. A , Volume 3 (1967/1968)". Publications of the Research Institute for Mathematical Sciences. 3 (3). 1967. doi:10.2977/prims/1195195460. ISSN   0034-5318.
  13. ↑ Mackay M, Mathieson A (January 1963). "The structure of α-bromo-isotutinone". Tetrahedron Letters. 4 (21): 1399–1403. doi:10.1016/s0040-4039(01)90840-8. ISSN   0040-4039.
  14. ↑ Okuda T, Yoshida T (January 1965). "The absolute configuration of tutin". Tetrahedron Letters. 6 (26): 2137–2142. doi:10.1016/s0040-4039(00)90167-9. ISSN   0040-4039.
  15. ↑ Okuda T, Yoshida T (December 1967). "The correlation of coriamyrtin and tutin, and their absolute configurations". Chemical & Pharmaceutical Bulletin. 15 (12): 1955–1965. doi: 10.1248/cpb.15.1955 . PMID   5590701.
  16. 1 2 3 4 5 Easterfield TH, Aston BC (1901). "XI.—Tutu. Part I. Tutin and coriamyrtin". J. Chem. Soc., Trans. 79: 120–126. doi:10.1039/ct9017900120. ISSN   0368-1645.
  17. ↑ Wakamatsu K, Kigoshi H, Niiyama K, Niwa H, Yamada K (January 1986). "Stereocontrolled total synthesis of (+)-tutin and (+)-asteromurin a, toxic picrotoxane sesquiterpenes". Tetrahedron. 42 (20): 5551–5558. doi:10.1016/s0040-4020(01)88159-x. ISSN   0040-4020.
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  19. ↑ Cheng CH, Datson PM, Hilario E, Deng CH, Manako KI, McNeilage M, et al. (2019-09-05). "Genomic predictions in diploid Actinidia chinensis (kiwifruit)". European Journal of Horticultural Science. 84 (4): 213–217. doi: 10.17660/ejhs.2019/84.4.3 . ISSN   1611-4426.
  20. ↑ Larsen L, Joyce NI, Sansom CE, Cooney JM, Jensen DJ, Perry NB (June 2015). "Sweet Poisons: Honeys Contaminated with Glycosides of the Neurotoxin Tutin". Journal of Natural Products. 78 (6): 1363–1369. doi:10.1021/acs.jnatprod.5b00241. PMID   25993882.
  21. 1 2 Ogilvie SC, Sam S, Barun A, Van Schravendijk-Goodman C, Doherty J, Waiwai J, et al. (2019-12-07). "Investigation of tutin, a naturally-occurring plant toxin, as a novel, culturally acceptable rodenticide in New Zealand". New Zealand Journal of Ecology. 43 (3). doi: 10.20417/nzjecol.43.37 . hdl: 10182/11803 . ISSN   0110-6465.
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  24. ↑ Hibbs RE, Gouaux E (June 2011). "Principles of activation and permeation in an anion-selective Cys-loop receptor". Nature. 474 (7349): 54–60. doi:10.1038/nature10139. PMC   3160419 . PMID   21572436.
  25. 1 2 McNaughton DE, Goodwin RM (27 June 2008). Reducing the threat Tutu toxic tutu honey poses to the New Zealand beekeeping industry and consumers. Hort Research Client Report (Report). Food Research Institute of New Zealand. 24884.
  26. 1 2 Fields BA, Reeve J, Bartholomaeus A, Mueller U (October 2014). "Human pharmacokinetic study of tutin in honey; a plant-derived neurotoxin". Food and Chemical Toxicology. 72: 234–241. doi:10.1016/j.fct.2014.07.032. PMID   25084484.
  27. ↑ Porter LA (August 1967). "Picrotoxinin and related substances". Chemical Reviews. 67 (4): 441–464. doi:10.1021/cr60248a004. PMID   4859924.
  28. ↑ Palmer-Jones T (1947). "A recent outbreak of honey poisoning. 3. The toxicology of the poisonous honey and the antagonism of tutin, mellitoxin, and picrotoxin by barbiturates". New Zealand Journal of Science and Technology, Section A. 29: 121–125. S2CID   90658098.
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