Cerberin is a type of cardiac glycoside, a steroidal class found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree (Cerbera odollam) and the sea mango (Cerbera manghas). This class includes digitalis-like agents, channel-blockers that as a group have found historic uses as cardiac treatments, but which at higher doses are extremely toxic; in the case of cerberin, consumption of the C. odollam results in poisoning with presenting nausea, vomiting, and abdominal pain, often leading to death. The natural product has been structurally characterized, its toxicity is clear—it is often used as an intentional human poison in third-world countries, and accidental poisonings with fatalities have resulted from individuals even indirectly consuming the agent—but its potentially therapeutic pharmacologic properties are very poorly described.
Digitoxigenin, the cardenolide substructure of cerberin, with the tetracyclic array of all-carbon steroid rings at its core, to which is attached the butenolide-type, oxygen-containing lactone substituent.
Cerberin, like all cardiac glycosides, has as its core a steroid-type set of four carbocycles (all-carbon rings). In cerberin, this steroid core is connected, first, to a separate oxygen-containing lactone ring (shown here, upper right of box), and second, to a sugar substituent (shown in infobox structure, left of image).[2]
There are two types of cardiac glycosides depending on the characteristics of the lactonemoiety. Cerberin, with its five-membered ring, belongs to the cardenolide class;[2] cardenolides are 23-carbon steroids with methyl groups at positions 10 and 13 of the steroid ring system, and the appended five-membered butenolide-type of lactone at C-17.[citation needed]
Many types of sugars can be attached to cardiac glycosides; in the case of cerberin, it is an O-acetylated derivative of α-L-thevetose, which is itself a derivative of L-glucose (6-deoxy-3-O-methyl-α-L-glucopyranose).[citation needed] The cardenolide substructure to which the sugar is attached has also been independently characterised, and can be referred to as digitoxigenin (see image), hence, cerberin is, synonymously, (L-2′-O-acetylthevetosyl)digitoxigenin. As well, the non-acetylated structure was independently discovered and named neriifolin, and so cerberin is, synonymously, 2′-acetylneriifolin.[citation needed]
The literature on cerberin toxicity, per se, remains sparse; unless otherwise specifically indicated, the following is general information regarding cardiac glycoside toxicity, with an emphasis on information from cardenolides (i.e., steroid natural products bearing the same digitoxigenin substructure).
In poisoning situations, those who are poisoned by ingesting cardiac glycosides experience, within an hour, a variety of gastrointestinal and cardiac symptoms.[citation needed] For cerberin, these have been noted to include nausea, vomiting, and abdominal pain.[3] Forensic sources indicate presentations for cardiac toxin poisonings that additionally include burning sensations in the mouth, diarrhea, headache, dilated pupils, irregular beating of the heart, and drowsiness; coma and death most often eventually follow.[4][5] There is no clear, reported correlation between the dose and mortality (see below); death often occurs after 3–6 hours.[3]
A historic, reported lethal dose of cerberin in dog is 1.8mg/kg, and in cat 3.1mg/kg; that is, it is very low.[1] Hence, eating the core of a fruit from the tree is sufficient for a human to receive a lethal dose,[citation needed] and consumption of the raw leaves of related oleander species has resulted in death.
There is significant evidence both from Cerbera and from related species, with regard to lethal poisonings.[3] Individual cases of poisoning from Cerbera, Nerium (oleander), and related species[6] are documented including direct and indirect, and intentional and unintentional ingestion.[3] In one case of accidental poisoning, two vegans in Europe that were foraging for and ingesting wild plants died after consuming wild oleander.[7] In indirect cases, human consumption of crab, where the crustacean had earlier consumed plants producing cerberin or related cardenolides, fatalities are also known.[8][9]
The response of humans to cardiac glycosides in general often depends on the tissue, exposure time and the dose.[citation needed] These toxins act mainly on the heart, either directly or through the nerves. Ouabain and digoxin have half-lives of about 20 and 40 hours, respectively,[citation needed] hence, for these agents, a few days with constant dosing are required before a steady state concentration is reached in tissues.[dubious–discuss][citation needed] The concentration of a cardioactive agent at steady state is called the therapeutic plasma concentration; for digoxin this value, in ng/mL, lies in the low single digits.[citation needed] When this value is exceeded, the dose can be toxic or life-threatening.[citation needed] Because of the long half-lives of cardiac glycosides, days might pass before plasma concentrations decrease to safe levels.[citation needed] The therapeutic index of cardiac glycosides is ≈2;[citation needed] this is quite narrow, indicating that only a small dose is needed for the compound to be toxic.[10]
There are reports that treatment with potassium ion can be used to counter the toxic effects of cerberin,[citation needed] and gastric lavage may also be applied.[citation needed] Even so, cases of direct and indirect poisoning often are fatal, even when the nature and source of the toxin are rapidly identified.[8][9]
Metabolism
Very little is known about the metabolism of cerberin. For the related digoxin, another cardiac glycoside, it is in largest part excreted unchanged by the kidneys (60-80%), with the remaining mostly metabolised by the liver.[citation needed] The half-life for digoxin is 36–48 hours for people with a normal renal function and up to 6 days for people with a compromised renal function.[citation needed] This makes the renal function an important factor in the toxicity of digoxin and perhaps for cerberin as well.[11]
Mechanism of action
There is very little formal, modern published information on the mechanism of action of cerberin.
Cerberin, as a cardiac glycoside, is seen as binding to and inhibiting the cellular Na+/K+ -ATPase, because it binds to the alpha-subunit of the enzyme. This is the catalytic moiety. There are also a beta- and FXYD subunits. These two subunits influence the affinity of cerberin to Na+/K+ -ATPase. The expression of the beta- and FXYD-subunit is tissue-specific. Because of this, cerberin will have different effects in different tissues. When cerberin binds to the Na+/K+-ATPase the conformation of the enzyme changes. This will lead to the activation of signal transduction pathways in the cell.[2] A detailed description of the effects of cerberin in the cell is given below.
Na+/K+-ATPase pump
Na+/K+-ATPase is an ion transport system of sodium and potassium ions and requires energy. It is often used in many types of cellular systems. Sodium ions move out of the cell and potassium ions enter the cell (3:2) with the aid of this pump. During the transport of these ions, the enzyme undergoes several changes in conformation. Including a phosphorylation and dephosphorylation step.[12]
The transport of Na+ and K+ is important for cell survival. Cardiac glycosides, such as cerberin, alter the transport of ions against their gradient. Cerberin is able to bind to the extracellular part of the Na+/K+-ATPase pump and can block the dephosphorylation step. Due to this inhibition it is impossible to transport sodium and potassium across the membrane and results in raising intracellular concentration of Na+.
Na+/Ca2+-exchanger
Accumulation of intracellular sodium ions cause an increase of intracellular calcium. This is because the calcium-sodium exchange pump’s activity decreases. The calcium-sodium exchange pump exchanges Ca2+ and Na+ without the use of energy.[13] This exchanger is essential for maintaining sodium and calcium homeostasis. The exact mechanism by which this exchanger works is unclear. It is known that calcium and sodium can move in either direction across the membrane of muscle cells. It is also known that three sodium ions are exchanged for each calcium and that an increase in intracellular sodium concentration through this exchange mechanism leads to an increase in intracellular calcium concentration. As intracellular sodium increases, the concentration gradient driving sodium into the cell across the exchanger is reduced. As a result, the activity of the exchanger is reduced, which decreases the movement of calcium out of the cell.[citation needed]
Thus by inhibiting the Na+/K+-ATPase, cardiac glycosides cause intracellular sodium concentration to increase. This leads to an accumulation of intracellular calcium via the Na+/Ca2+-exchange system with the following effects:
In the heart, increased intracellular calcium causes more calcium to be released, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).
Inhibition of the Na+/K+-ATPase in vascular smooth muscle causes depolarization, which causes smooth muscle contraction.[citation needed]
The conformational change of Na+/K+-ATPase plays not only a role in the contraction of muscles, but also in cell growth, cell motility and apoptosis. Due to de binding of cerberin, specific second messengers can be activated. After a cascade of cellular interactions nuclear transcription factors binds to the DNA and new enzymes will be made. This enzymes can for example play a role in cell proliferation.[2][subscription required]
Efficacy
There is very little formal, modern published information on the pharmacological actions of cerberin. One primary source reports that its ingestion results in electrocardiogram (ECG) changes, such as various types of bradycardia (e.g., sinus bradycardia), AV dissociation, and junctional rhythms; second-degree sinoatrial block and nodal rhythm are also described.[3]
In the case of digitalis administration, ST depression or T wave inversion may occur without indicating toxicity; however, PR interval prolongation indicate toxicity.[14]
There are no clearly established therapeutic uses of the title compound, cerberin. Digitalis compounds, related cardiac glycosides, function through the inhibition of the Na+/K+-ATPase-pump,[2] and have been widely used for in the treatment of chronic heart failure and arrhythmias; although newer and more efficacious treatments for heart failure are available, digitalis compounds are still used.[citation needed] Some cardiac glycosides have been shown to have antiproliferative and apoptotic effects, and are therefore of interest as potential agents in cancer chemotherapy;[2] there is a single report to date of possible antiproliferative activity of cerberin.[15][16]
Further reading
Carlier, J.; Guitton, J.; Bévalot, F.; Fanton, L.; Gaillard, Y. (2014). "The principal toxic glycosidic steroids in Cerbera manghas L. seeds: identification of cerberin, neriifolin, tanghinin and deacetyltanghinin by UHPLC-HRMS/MS, quantification by UHPLC-PDA-MS". J. Chromatogr. B. 962: 1–8. doi:10.1016/j.jchromb.2014.05.014. PMID24878878.
Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses are as treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.
Digitalis is a genus of about 20 species of herbaceous perennial plants, shrubs, and biennials, commonly called foxgloves.
The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.
Digoxin, sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is one of the oldest medications used in the field of cardiology. It works by increasing myocardial contractility, increasing stroke volume and blood pressure, reducing heart rate, and somewhat extending the time frame of the contraction. Digoxin is taken by mouth or by injection into a vein. Digoxin has a half life of approximately 36 hours given at average doses in patients with normal renal function. It is excreted mostly unchanged in the urine.
Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.
Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasionally when severe it can cause palpitations, muscle pain, muscle weakness, or numbness. Hyperkalemia can cause an abnormal heart rhythm which can result in cardiac arrest and death.
Ouabain or also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ouabain is a cardiac glycoside and in lower doses, can be used medically to treat hypotension and some arrhythmias. It acts by inhibiting the Na/K-ATPase, also known as the sodium-potassium ion pump. However, adaptations to the alpha-subunit of the Na+/K+-ATPase via amino acid substitutions, have been observed in certain species, namely some herbivore- insect species, that have resulted in toxin resistance.
Cerbera odollam is a tree species in the family Apocynaceae commonly known as the suicide tree, pong-pong, mintolla, and othalam. It bears a fruit known as othalanga that yields a potent poison that has been used for suicide and murder.
Bufagin is a toxic steroid C24H34O5 obtained from toad's milk, the poisonous secretion of a skin gland on the back of the neck of a large toad (Rhinella marina, synonym Bufo marinus, the cane toad). The toad produces this secretion when it is injured, scared or provoked. Bufagin resembles chemical substances from digitalis in physiological activity and chemical structure.
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). A single calcium ion is exported for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.
A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting. Cardenolides are toxic to animals through inhibition of the enzyme Na+/K+‐ATPase, which is responsible for maintaining the sodium and potassium ion gradients across the cell membranes.
k-Strophanthidin is a cardenolide found in species of the genus Strophanthus. It is the aglycone of k-strophanthin, an analogue of ouabain. k-strophanthin is found in the ripe seeds of Strophanthus kombé and in the lily Convallaria.
The Bowditch effect, also known as the Treppe phenomenon and the Treppe effect, is an autoregulation method by which myocardial tension increases with an increase in heart rate. It was first observed by Henry Pickering Bowditch in 1871.
Digoxin immune fab or digoxin-specific antibody is an antidote for overdose of digoxin. It is made from immunoglobulin fragments from sheep that have already been immunized with a digoxin derivative, digoxindicarboxymethoxylamine (DDMA). Its brand names include Digibind (GlaxoSmithKline) and DigiFab.
Oleandrin is a cardiac glycoside found in the poisonous plant oleander. As a main phytochemical of oleander, oleandrin is associated with the toxicity of oleander sap, and has similar properties to digoxin.
Arenobufagin is a cardiotoxic bufanolide steroid secreted by the Argentine toad Bufo arenarum. It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue.
Antiarins are cardiac glycoside poisons produced by the upas tree. There are two forms, α-antiarin and β-antiarin.
Convallatoxin is a glycoside extracted from Convallaria majalis.
Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure
Calotropin is a toxic cardenolide found in plants in the family Asclepiadoideae. In extreme cases, calotropin poisoning can cause respiratory and cardiac failure. Accidental poisoning is common in livestock who have ingested milkweed. Calotropin is commonly stored as a defense mechanism by insects that eat milkweeds as their main food source.
References
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1 2 3 4 5 6 Prassas, I.; Diamandis, E. P. (2008). "Novel of therapeutic applications of cardiac glycosides". Nature Reviews Drug Discovery. 7 (11): 926–930. doi:10.1038/nrd2682. PMID18948999.
1 2 3 4 5 Gaillarda, Y.; Krishnamoorthyb, A.; Bevalot, F. (12 August 2004). "Cerbera odollam: a 'suicide tree' and cause of death in the state of Kerala, India". Journal of Ethnopharmacology. 95 (2–3): 123–126. doi:10.1016/j.jep.2004.08.004. PMID15507323.
↑ Nageshkumar G. Rao, 1999, Textbook of Forensic Medicine and Toxicology, pp. 425-434, New Delhi, DL, IND:Jaypee Brothers Medical Publishers, ISBN8171797350, see , accessed 22 June 2015.
↑ Krishan Vij, 1999, "Cardiac Poisons (Ch. 42)," in Textbook of Forensic Medicine and Toxicology: Principles and Practice, 5th Edn., pp. 529-530, Gurgaon, HR, IND:Elsevier India, ISBN8131226840, see , accessed 22 June 2015.
↑ Papi, Luigi; Luciani, Alessandro Bassi; Forni, David; Giusiani, Mario (2012). "Unexpected Double Lethal Oleander Poisoning". The American Journal of Forensic Medicine and Pathology. 33 (1): 93–97. doi:10.1097/PAF.0b013e31822d33d4. PMID21926903.
1 2 Maillaud, C.; Lefebvre, S.; Sebat, C.; Barguil, Y.; Cabalion, P.; Cheze, M.; Hnawia, E.; Nour, M.; Durand, F. (2010). "Double Lethal Coconut Crab (Birgus Latro L.) Poisoning". Toxicon. 55 (1): 81–86. doi:10.1016/j.toxicon.2009.06.034. PMID19591858.
1 2 Maillaud, C.; Barguil, Y.; Mikulski, M.; Cheze, M.; Pivert, C.; Deveaux, M.; Lapostolle, F. (2012). "First Successful Curative Use of Digoxin-specific Fab Antibody Fragments in a Life-threatening Coconut Crab (Birgus Latro L.) Poisoning". Toxicon. 60 (6): 1013–017. doi:10.1016/j.toxicon.2012.06.017.
↑ Doering W, König E, Sturm W (1977). "Digitalisintoxikation: Wertigkeit klinischer und electrokardiographischer Befunde im Vergleich zur Digoxinkonzentration im Serum. 1. Teil: Patienten mit Digitalisinduzierten Rhythmusstörungen" [Digitalis intoxication: specificity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl.)]. Zeitschrift für Kardiologie (in German). 66 (3): 121–128. PMID857452.
↑ Laphookhieo, S.; Cheenpracha, S.; Karalai, C.; Chantrapromma, S.; Rat-a-Pa, T.; Ponglimanont, C.; Chantrapromma, K. (2004). "Cytotoxic cardenolide glycoside from the seeds of Cerbera odollam". Phytochemistry. 65: 507–510. doi:10.1016/j.phytochem.2003.10.019.
↑ Newman, R. A.; Yang, P.; Pawlus, A. D.; Block, K. I. (2008). "Cardiac Glycosides as Novel Cancer Therapeutic Agents". Molecular Interventions. 8 (1): 36–49. doi:10.1124/mi.8.1.8. PMID18332483.
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