{{Chembox <!-- Images --> | ImageFile = Zygacine.svg | ImageSize = 200px | ImageFile1 = Zygacine model.png | ImageSize1 = 200px <!-- Names --> | IUPACName = (5ξ,8ξ,9ξ,12ξ,14ξ)-4,14,15,16,20-Pentahydroxy-4,9-epoxycevan-3-yl acetate | OtherNames = Cevane-3β,4β,14,15α,16β,20-hexol, 4,9-epoxy-, 3-acetate <!-- Sections --> | Section1 = {{Chembox Identifiers | CASNo = 2777-79-9 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = BAY5Z5MC9Z | ChemSpiderID = 10181195 | PubChem = 3083781 | SMILES = [H][C@@]12C[C@]34O[C@]5(O)[C@H](CC[C@@]3(C)[C@]5([H])CC[C@@]4([H])[C@]1(O)[C@@H](O)[C@H](O)[C@@]1([H])[C@@]2([H])CN2C[C@@H](C)CC[C@@]2([H])[C@@]1(C)O)OC(C)=O | StdInChI=1S/C29H45NO8/c1-14-5-8-20-26(4,34)22-16(13-30(20)12-14)17-11-27-19(28(17,35)24(33)23(22)32)7-6-18-25(27,3)10-9-21(37-15(2)31)29(18,36)38-27/h14,16-24,32-36H,5-13H2,1-4H3/t14-,16-,17?,18?,19?,20-,21?,22+,23?,24?,25-,26+,27?,28?,29?/m0/s1 | StdInChIKey = IGDRXLIXNAWBBF-UFWHGLMDSA-N }} | Section2 = {{Chembox Properties | C=29|H=45|N=1|O=8 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} | Section3 = {{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}
'''Zygacine''' is a steroidal alkaloid of the genera ''Toxicoscordion'', ''Zigadenus'', ''Stenanthium'' and ''Anticlea'' of the family Melanthiaceae.<ref name=":1">{{Cite web|url=http://calscape.org/Toxicoscordion-venenosum-()|title=Death Camas, Toxicoscordion venenosum|website=calscape.org|language=en|access-date=2018-05-15}}</ref> These plants are commonly known and generally referred to as death camas. Death camas is prevalent throughout North America and is frequently the source of poisoning for outdoor enthusiasts and livestock due to its resemblance to other edible plants such as the wild onion.<ref name=":1" /> Despite this resemblance, the death camas plant lacks the distinct onion odor and is bitter to taste.
The effects of zygacine consumption are lethal. Symptoms in humans include nausea, vomiting, slowed heart rate, low blood pressure and ataxia.<ref name=":2">Stegelmeier, Bryan L., Reuel Field, Kip E. Panter, Jeffery O. Hall, Kevin D. Welch, James A. Pfister, Dale R. Gardner et al. "Selected poisonous plants affecting animal and human health." In ''Haschek and Rousseaux's Handbook of Toxicologic Pathology (Third Edition)'', pp. 1259-1314. 2013.</ref> Poisoned animals suffer from loss of appetite, lack of coordination, digestive and excretory disorders, labored breathing, racing heartbeat and frequently death.<ref name=":2" />
Suggested treatment of poisoning in humans include administering dopamine and atropine to the patient.<ref name=":4">{{Cite web|url=https://www.uptodate.com/contents/renal-actions-of-dopamine|title=UpToDate|website=www.uptodate.com|access-date=2018-05-15|archive-date=2023-12-09|archive-url=https://web.archive.org/web/20231209010243/https://www.uptodate.com/contents/renal-actions-of-dopamine|url-status=dead}}</ref> For animals, treatment consists of atropine, picrotoxin and activated charcoal.<ref name=":5">{{Cite web|url=https://csuvth.colostate.edu/poisonous_plants/Plants/Details/36|title=Guide to Poisonous Plants – College of Veterinary Medicine and Biomedical Sciences – Colorado State University|website=csuvth.colostate.edu|access-date=2018-05-15}}</ref>
== History == Scientists first attempted to determine the toxic ingredient(s) of alkaloid extracts of ''Zygadenus'' plants in 1913.<ref name=":3">Kupchan, S. Morris. "Veratrum alkaloids. XXX. 1 The structure and configuration of zygadenine2." ''Journal of the American Chemical Society'' 81, no. 8 (1959): 1925-1928.</ref> They were able to isolate zygadenine, the alkamine present in alkaloids of the genus ''Zigadenus''.<ref name=":3" /> The minimal pharmacological activity of zygadenine led to subsequent investigations of ''Zygadenus venenosus'' and ''Zygadenus paniculatus'' which revealed that zygacine was one of the primary toxic components.<ref name=":3" /> Although it was first isolated in 1913, the structure and configuration of zygacine weren't reported until 1959.<ref>Majak, Walter, Ruth E. McDiarmid, Walter Cristofoli, Fang Sun, and Michael Benn. "Content of zygacine in Zygadenus venenosus at different stages of growth." ''Phytochemistry'' 31, no. 10 (1992): 3417-3418.</ref>
Zygacine poisoning via ingestion of death camas had been reported in both livestock and humans as early as the nineteenth century.<ref>{{cite book |last=Chesnut |first=Victor King |chapter=Preliminary Catalogue of Plants Poisonous to Stock |title=Fifteenth Annual report of the Bureau of Animal Industry for the Year 1898 |publisher=Government Printing Office |year=1898 |page=396}}</ref> It has been for many years – and continues to be – responsible for the poisonings and deaths of many types of livestock including sheep, cattle, horses, pigs and fowl.<ref>Panter, K. E., and L. F. James. "Death camas--early grazing can be hazardous." ''Rangelands Archives'' 11, no. 4 (1989): 147-149.</ref> A one-time loss of 500 sheep was reported in 1964<ref>Kingsbury, John M. "Poisonous plants of the United States and Canada." ''Soil Science'' 98, no. 5 (1964): 349.</ref> and in 1987, 250 sheep died from death camas poisoning.<ref>Panter, K.E., M.H. Raiphs, R.A. Smart, and B. Duelke. 1987. Death camas poisoning in sheep: A case report. Vet, and Human Tox. 29:45-48.</ref> Poisonings generally occur in the early spring when the death camas plant is most abundant and other food sources for livestock are limited.<ref name="Welch 1650–1657">{{Cite journal|last1=Welch|first1=K. D.|last2=Panter|first2=K. E.|last3=Gardner|first3=D. R.|last4=Stegelmeier|first4=B. L.|last5=Green|first5=B. T.|last6=Pfister|first6=J. A.|last7=Cook|first7=D.|date=2011-05-01|title=The acute toxicity of the death camas (Zigadenus species) alkaloid zygacine in mice, including the effect of methyllycaconitine coadministration on zygacine toxicity|url=https://www.animalsciencepublications.org/publications/jas/articles/89/5/1650|journal=Journal of Animal Science|language=en|volume=89|issue=5|pages=1650–1657|doi=10.2527/jas.2010-3444|pmid=21521823|s2cid=4693834|issn=1525-3163|url-access=subscription|archive-date=2017-03-18|access-date=2017-03-17|archive-url=https://web.archive.org/web/20170318003246/https://www.animalsciencepublications.org/publications/jas/articles/89/5/1650|url-status=dead}}</ref> Sheep seem to be poisoned most often due to their grazing behavior as they pull up and consume the entire plant.<ref name=":2" /> Moist conditions are more conducive to cattle poisoning as it makes it easier to extract the plant from the soil.<ref name=":2" /> Humans have also fallen victim to zygacine poisoning by mistaking the death camas for other edible plants. In 1994, a man presented to the emergency department with gastrointestinal symptoms, a depressed heart rate and low blood pressure after inadvertently eating plant material derived from a species of ''Zigadenus''.<ref name=":0">{{Cite journal|last=Heilpern|first=Katherine L|date=1995-02-01|title=Zigadenus Poisoning|journal=Annals of Emergency Medicine|volume=25|issue=2|pages=259–262|doi=10.1016/S0196-0644(95)70336-5|pmid=7832360}}</ref> He recovered after being treated.
== Toxicity == Zygacine is a highly potent compound with an {{LD50}} of 2.0 ± 0.2 mg/kg when administered intravenously and 132 ± 21 mg/kg when administered orally to mice.<ref name="Welch 1650–1657" /> The lethal dose conversions for a 60 kg human, 600 kg cow and 80 kg sheep are included in the table below. {| class="wikitable" |+LD<sub>50</sub> of zygacine !Subject !Human (60 kg) !Cattle (600 kg) !Sheep (80 kg) |- |IV administration |108–132 mg |1.08–1.32 g |144–176 mg |- |Oral administration |6.66–9.18 g |66.60–91.80 g |8.88–12.24 g |} General symptoms of zygacine poisoning among humans and animals alike include but are not limited to gastrointestinal and cardiovascular ailments such as nausea, vomiting, diarrhea and irregular heartbeat.<ref name=":0" />
Within an hour of ingesting the toxic death camas plant, a human will begin to experience nausea, vomiting, abdominal cramping and diarrhea.<ref name=":0" /> Other symptoms include low heart rate and blood pressure as well as ataxia and muscle spasms.<ref name=":0" />
Initial signs of zygacine poisoning in animals include frothy salivation around the mouth, followed by nausea and vomiting.<ref name=":6">Panter, Kip E., Kevin D. Welch, and Dale R. Gardner. "Poisonous plants: biomarkers for diagnosis." In ''Biomarkers in Toxicology'', pp. 563-589. 2014.</ref> Severely poisoned animals will suffer from a loss in appetite, lack of coordination and depression.<ref name=":2" /> Sheep, in particular, will stand with their heads and ears dropped with their backs are arched.<ref name=":2" /> Intestinal peristalsis, a condition characterized by involuntary movement of the muscles in the digestive tract, results in frequent defecation and urination.<ref name=":6" /> Fatally poisoned animals develop a weak and rapid pulse and labored breathing.<ref name=":6" /> The shuddering struggle to breathe may be confused with convulsions.<ref name=":6" />
== Mechanism == Zygacine is a steroidal alkaloid of the veratrum type.<ref>{{Cite web|url=https://poisonousplants.ansci.cornell.edu/toxicagents/steroid.html|title=Cornell University Department of Animal Science|website=poisonousplants.ansci.cornell.edu|access-date=2018-05-15}}</ref> Veratrum alkaloid compounds act by attaching to voltage-gated sodium ion channels, altering their permeability.<ref name=":7">Furbee, Brent. "Neurotoxic plants." In ''Clinical Neurotoxicology: Syndromes, Substances, Environments''. Elsevier Inc., 2009.</ref> Veratrum alkaloids cause affected sodium channels to reactivate 1000x slower than unaffected channels.<ref name=":7" /> They also block inactivation of sodium channels and change their activation threshold so they remain open even at resting potential.<ref name=":7" /> As a result, sodium concentrations within the cell rise, leading to increased nerve and muscle excitability.<ref name=":0" /> This biochemical activity causes muscle contractions, repetitive firing of the nerves and an irregular heart rhythm from stimulation of vagal nerves which control the parasympathetic functions of the heart, lungs and digestive tract.<ref name=":0" />
== Treatment == There is no antidote for zygacine poisoning so only the symptoms arising from poisoning in humans are usually treated, of which bradycardia and hypotension are prioritized. These symptoms are initially treated with atropine, a muscarinic receptor antagonist.<ref>McLendon K, Preuss CV. Atropine. [Updated 2023 Jun 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470551/</ref> In a case study in which atropine was not sufficient, hypotension and bradycardia were successfully treated using dopamine.<ref>West, Patrick, and B. Zane Horowitz. "Zigadenus poisoning treated with atropine and dopamine." ''Journal of Medical Toxicology'' 5, no. 4 (2009): 214.</ref> Dopamine increases renal sodium excretion, blood pressure and the heart rate.<ref>Bhatt-Mehta, Varsha; Nahata, Milap C. (1989-09-10). "Dopamine and Dobutamine in Pediatric Therapy". ''Pharmacotherapy: the Journal of Human Pharmacology and Drug Therapy''. '''9''' (5): 303–314.</ref>
For animals, reported effective treatment of zygacine poisoning consists of injection of 2 mg of atropine sulfate and 8 mg of picrotoxin per 45 kg of body weight.<ref name=":5" /> Intravenous fluid therapy is used to increase blood pressure.<ref name=":5" /> A stomach tube can be used to relieve stomach pressure in bloated animals.<ref name=":5" />
== References == <references />
Category:Steroidal alkaloids Category:Toxins Category:Plant toxins Category:Heterocyclic compounds with 6 rings Category:Nitrogen heterocycles