Convallatoxin

Last updated
Convallatoxin
Convallatoxin.svg
Convallatoxin 3D BS.png
Names
IUPAC name
5,14-Dihydroxy-19-oxo-3β-(α-L-rhamnopyranosyloxy)-5β-card-20(22)-enolide
Systematic IUPAC name
(1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-3a,5a-Dihydroxy-11a-methyl-1-(5-oxo-2,5-dihydrofuran-3-yl)-7-{[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexadecahydro-9aH-cyclopenta[a]phenanthrene-9a-carbaldehyde
Other names
Strophanthin 3alpha-1-rhamnoside; Strophanthidin alpha-l-rhamnopyranoside; Strophanthidin a-l-rhamnopyranoside; Corglycon (Russian: Коргликон); 20(22),5beta-cardenolid-19-al-3beta,5beta,14beta-triol-3beta-d-[a-1-rhamnopyranoside]; 5Beta,20[22]-cardenolide-19-one-3beta,5alpha,14-triol-3-[6-deoxy-alpha-l-mannopyranosyl]; 3Beta,5alpha,14-trihydroxy-19-oxo-5beta,20[22]-cardenolide-3-[6-deoxy-alpha-l-mannopyranosyl]
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.007.352 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 208-086-3
PubChem CID
UNII
  • InChI=1S/C29H42O10/c1-15-22(32)23(33)24(34)25(38-15)39-17-3-8-27(14-30)19-4-7-26(2)18(16-11-21(31)37-13-16)6-10-29(26,36)20(19)5-9-28(27,35)12-17/h11,14-15,17-20,22-25,32-36H,3-10,12-13H2,1-2H3/t15-,17-,18+,19-,20+,22-,23+,24+,25-,26+,27-,28-,29-/m0/s1 X mark.svgN
    Key: HULMNSIAKWANQO-JQKSAQOKSA-N X mark.svgN
  • InChI=1/C29H42O10/c1-15-22(32)23(33)24(34)25(38-15)39-17-3-8-27(14-30)19-4-7-26(2)18(16-11-21(31)37-13-16)6-10-29(26,36)20(19)5-9-28(27,35)12-17/h11,14-15,17-20,22-25,32-36H,3-10,12-13H2,1-2H3/t15-,17-,18+,19-,20+,22-,23+,24+,25-,26+,27-,28-,29-/m0/s1
    Key: HULMNSIAKWANQO-JQKSAQOKBT
  • O=C\1OC/C(=C/1)[C@H]2CC[C@@]6(O)[C@]2(C)CC[C@H]4[C@H]6CC[C@]5(O)C[C@@H](O[C@@H]3O[C@H]([C@H](O)[C@@H](O)[C@H]3O)C)CC[C@]45C=O
Properties
C29H42O10
Molar mass 550.645 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Convallatoxin is a glycoside extracted from Convallaria majalis .

Contents

History

Convallatoxin is a natural cardiac glycoside that can be found, among others, in the plant lily of the valley (Convallaria majalis). Legend says that Apollo gave this plant to Asclepios, the Greek god of healing. [1] Lily of the valley has indeed been used medicinally to treat illness, [2] all going back to medieval times. Convallatoxin has a similar therapeutic target and effect as digitalis, so it was used by medieval herbalists as a substitute for foxglove in treatment. [3] [4] It is mostly administered because it strengthens the heartbeat, while also slowing and regulating the heart rate. [3] In 2011, the lily of the valley was used in the US television show Breaking Bad. This made the plant, and its compound convallatoxin, quite well known by the general public as fatal. [5]

Structure and reactivity

The systematic name of the organic compound convallatoxin is as follows: (1R,3aS,3bR,5aS,7S,9aS,9bS,11aR)-3a,5a-dihydroxy-11a-methyl-1-(5-oxo-2,5-dihydrofuran-3-yl)-7-{[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy}hexadecahydro-9aH-cyclopenta[a]phenanthrene-9a-carbaldehyde. A shorter semisystematic IUPAC name is 5,14-dihydroxy-19-oxo-3β-(α-L-rhamnopyranosyloxy)-5β-card-20(22)-enolide. The structure of convallatoxin consists of strophanthidin and has a 6-deoxy-α-L-mannopyranosyl group attached at position 3. [6]

Convallatoxin can donate a hydrogen bond at five places and it can accept a hydrogen bond on ten accounts. [6] Its melting point lies between 235 and 242 degrees Celsius and the compound is soluble in alcohol, acetone and slightly in chloroform, ethyl acetate and water. [7]

Since convallatoxin is structurally similar to digoxin, research has been done to determine if convallatoxin in serum can be detected with LOCI digoxin assays. [4] This showed that the compound has significant cross-reactivity with the used antibody and that it causes bidirectional interference in the digoxin assay. So, convallatoxin can indeed be detected with a LOCI digoxin assay. It may also be possible that convallatoxin cross-reacts with the antidigoxin antibody used in other commercially available digoxin assays, but this should be investigated further. Furthermore, the antigen Digibind does also bind convallatoxin in vitro. This could possibly be used in treatment of convallatoxin poisoning. [4]

Synthesis

Even though convallatoxin can be found in nature, it is also synthesized by manufacturers. This can be done via the Koenigs-Knorr method, [8] in which strophanthidin is glycosylated with 2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl bromide. [9] [10] These two compounds are the precursors of convallatoxin. After alkaline hydrolysis, extraction from strophanthidin residues and crystallization of isopropanol, the reaction product is liberated. This reaction product is convallatoxin. When using 10 grams of strophanthidin, 13.6 grams of convallatoxin can be produced. [9]

Mechanism of action and efficacy

Convallatoxin is a digitalis like compound (DLC), which is mainly used as a cardiac glycoside since it can inhibit the Na+,K+-ATPase in congestive heart failure or arrythmias, [11] [12] [13] [14] [15] which causes an inotropic effect, [14] [16] same as many other digitalis like compounds. The Na+,K+-ATPase creates the ion gradient between the intra- and extracellular domains of a cell. It does this by transporting three sodium ions out of and two potassium ions into the cell. [17] If the Na+,K+-ATPase is inhibited, sodium will accumulate in the cell, preventing the sodium-calcium exchanger to work during diastole. If calcium accumulates in cardiac myocytes, the uptake of calcium into the sarcoplasmic reticulum (SR) is increased. Thus, when stimulation of the cardiac muscle occurs, the SR releases higher levels of calcium, which increases the contractility of the myocytes. [17] The increased release of calcium also increases the refractory period of the atrioventricular (AV) node, regulating the heart beat cycle [18] in patients with arrythmia.

In lung, colon and breast cancer cells, convallatoxin shows great effects at nano doses. [15] [19] [20] [21] It has been shown to inhibit cell proliferation, invasion and migration of cancer cells. The underlying mechanisms of this are not fully known. However, it has been demonstrated that convallatoxin induces apoptosis and autophagy at a dose of 10 nM per 3 days. [13] It was also shown to inhibit angiogenesis through autophagy and apoptosis at concentrations of 2-4 nM. [13] Autophagy is induced in human cervical carcinoma cells, or HeLa cells by convallatoxin blocking the mTOR signalling pathway. This signalling pathway usually inhibits autophagy in cells. Convallatoxin induces apoptosis by increasing caspase-3 and PARP cleavage. These proteins induce programmed cell death when activated by cleavage. [13] It is not entirely clear if the induction of apoptosis and autophagy is related to the inhibitory effects of convallatoxin on the Na+, K+-ATPase pump. However, a dose of 10 nM convallatoxin can reduce A549 non small cell lung cancer cells by inhibiting the Na+,K+-ATPase. [15] [20] Numbers differ per experiment. In colon cancer a LD50 of 50 nM is shown. [19] In MCF-7 derived breast cancer cells an IC50 dose of 10 nM over a long time (exposure 24 h) show 27.65 ± 8.5 or over an even longer time (exposure 72 h), 5.32 ± 0.15 are observed. [21]

There are many more potential therapeutic uses for convallatoxin, for example against cystic fibrosis and neurodegenerative diseases. [22] It has also been demonstrated to inhibit viral infection and replication. [23] For example, convallatoxin can be used as a treatment for the Human Cytomegalovirus. It will inhibit the Na+-K+-ATPase pump which decreases the sodium concentration outside the cell, and thus limiting cotransport of methionine and sodium into the cell, disabling protein synthesis. [24] A dose of 0.01 μM already has a great efficacy against the cytomegalovirus, but at a dose of 50 nM or less a great potency is also shown that can last up to 4 hours. [24]

Convallatoxin is thus quite an efficient drug, showing effects with small doses in treatment of multiple diseases. It is excreted by P-glycoprotein and an affinity of 1.07 ± 0.24 mM and a Vmax of 5.2 ± 0.4 mmol mg/protein/min were determined. Excretion of convallatoxin is mainly by the kidneys (a clogP of about -0.7). [25] [26]

Metabolism

Convallatoxin is mainly metabolised in the liver by the conversion of convallatoxin into convallatoxol. [27] For this, the aldehyde (-CHO) group attached to C¬10 is reduced to an alcohol group (-CH2OH) by cytochrome P450 reductase (CYP450). [28] This is a phase I metabolism reaction. However, further modification through a phase II reaction of convallatoxin has not been found. [29] The reduction of convallatoxin increases its polarity, thus enabling the compound to be excreted more readily. This form of convallatoxin metabolism can be found in rats, however is not present in guinea pigs and only traces of convallatoxol can be found in cats. [30]

Toxicity

Convallatoxin has a very small therapeutic index (40-50 nM) i.e. the margin is narrow between a therapeutic dose and an overdose giving rise to symptoms of poisoning. Even so, the cytotoxicity of convallatoxin is mainly time-dependent.

At an increased plasma level, DLCs (including convallatoxin) toxicity symptoms include dizziness, fatigue, nausea, loss of appetite, vision disturbance, vomiting, hypertension, arrythmia, cardiac arrest, coma, abdominal pain and convulsions, heart failure or death. [11] [12] [25]

Effects on animals

On certain animals, convallatoxin has quite interesting effects. The lifespan of C. elegans , a nematode, can be expanded by convallatoxin. [31] About 20 μM of convallatoxin shows no toxicity and can expand the lifespan of the worm by 16.3% due to certain mechanisms, including improvement of pharyngeal pumping, locomotion, reduced lipofuscin accumulation and ROS. [31]

Where the convallatoxin has quite positive effects on nematodes, it is extra poisonous to cats. [32] It causes nephrotoxicity and acute renal failure, but at what dose exactly is not known. Symptoms are salivation, vomiting, anorexia and depression. It can be treated with dialysis, when diuresis is started before the acute renal failure. [32]

Related Research Articles

<span class="mw-page-title-main">Cardiac glycoside</span> Class of organic compounds

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.

<i>Digitalis</i> Genus of flowering plants in the family Plantaginaceae

Digitalis is a genus of about 20 species of herbaceous perennial plants, shrubs, and biennials, commonly called foxgloves.

<span class="mw-page-title-main">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

<span class="mw-page-title-main">Digoxin</span> Plant-derived medication

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.

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

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.

<span class="mw-page-title-main">Reactive oxygen species</span> Highly reactive molecules formed from diatomic oxygen (O₂)

In chemistry and biology, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (O2), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (O2H), superoxide (O2-), hydroxyl radical (OH.), and singlet oxygen. ROS are pervasive because they are readily produced from O2, which is abundant. ROS are important in many ways, both beneficial and otherwise. ROS function as signals, that turn on and off biological functions. They are intermediates in the redox behavior of O2, which is central to fuel cells. ROS are central to the photodegradation of organic pollutants in the atmosphere. Most often however, ROS are discussed in a biological context, ranging from their effects on aging and their role in causing dangerous genetic mutations.

<span class="mw-page-title-main">Ouabain</span> Chemical substance

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.

<span class="mw-page-title-main">Phytochemistry</span> Study of phytochemicals, which are chemicals derived from plants

Phytochemistry is the study of phytochemicals, which are chemicals derived from plants. Phytochemists strive to describe the structures of the large number of secondary metabolites found in plants, the functions of these compounds in human and plant biology, and the biosynthesis of these compounds. Plants synthesize phytochemicals for many reasons, including to protect themselves against insect attacks and plant diseases. The compounds found in plants are of many kinds, but most can be grouped into four major biosynthetic classes: alkaloids, phenylpropanoids, polyketides, and terpenoids.

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

Cerberin is a type of cardiac glycoside, a steroidal class found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. 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.

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.

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

Bufotalin is a cardiotoxic bufanolide steroid, cardiac glycoside analogue, secreted by a number of toad species. Bufotalin can be extracted from the skin parotoid glands of several types of toad.

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

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

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

Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus. It is a potent, selective, and cell-permeable protein kinase C inhibitor in vitro. And an efficacious antagonist of G-protein-coupled CB1 receptors. This molecule also exhibits anticancer qualities and it has served as a base for many potential novel drugs against cancer. Structurally, this molecule has two distinct conformations, one being a positively charged iminium form, and the other being an uncharged form, a pseudo-base.

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

Genistein (C15H10O5) is a naturally occurring compound that structurally belongs to a class of compounds known as isoflavones. It is described as an angiogenesis inhibitor and a phytoestrogen.

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

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 Chemical compound

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.

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

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.

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

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.

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

Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad Bufo gargarizans. It has similar effects to digitalis and is used in traditional Chinese medicine.

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

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

  1. ↑ Hill, K. "Guide to the Medicinal Plant Garden" (PDF). Indiana Medical History Museum.
  2. ↑ van der Bijl Jr., P; van der Bijl Sr., P (2012). "Cardiovascular Toxicities of Herbal Products: An Overview of Selected Compounds". Toxicology of Herbal Products. Cham, Switzerland: Springer Nature. pp. 363–383.
  3. 1 2 Breverton, T (2012). Breverton's Complete Herbal: A book of remarkable plants and their uses. London: Lyons Press.
  4. 1 2 3 Welsh, K J; Huang, R S P; Actor, J K; Dasgupta, A (2019-03-05). "Rapid Detection of the Active Cardiac Glycoside Convallatoxin of Lily of the Valley Using LOCI Gigoxin Assay". American Journal of Clinical Pathology. 142 (3): 307–312. doi:10.1309/AJCPCOXF0O5XXTKD. PMID   25125619.
  5. ↑ Schönsee, C (2018-04-16). "Convallatoxin - the toxin of wild garlic's deadly doppelgänger". University of Copenhagen. Retrieved 2019-03-04.
  6. 1 2 PubChem. "Convallatoxin". pubchem.ncbi.nlm.nih.gov. Retrieved 2019-03-23.
  7. ↑ Windholz, M (1976). The Merck Index: an encyclopedia of chemicals and drugs. Rahway, USA: Merck & Co. p. 323.
  8. ↑ Koenigs, W; Knorr, E (1901). "Ueber einige Derivate des Traubenzuckers un der Galactose". Berichte der Deutschen Chemischen Gesellschaft. 34 (1): 957–981. doi:10.1002/cber.190103401162.
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  14. 1 2 Cheng, CJ; Lin, CS; Chang, LW; Lin, SH (2006). "Perplexing hyperkalaemia". Nephrology Dialysis Transplantation. 21 (11): 3320–3323. doi:10.1093/ndt/gfl389. PMID   16968727.
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  16. ↑ Everett, JM; Konjima, YA; Davis, B; Wahed, A; Dasgupta, A (2015). "The iDigoxin assay is more sensitive than LOCI digoxin assay for rapid detection of convallatoxin, the active cardiac glycoside of lily of the valley". Annals of Clinical & Laboratory Science. 45 (3): 323–326.
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  18. ↑ Patel, S (2016). "Plant-derived cardiac glycosides: Role in heart ailments and cancer management". Biomedicine & Pharmacotherapy. 84: 1036–1041. doi:10.1016/j.biopha.2016.10.030. PMID   27780131.
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  21. 1 2 Kaushik, V; Azad, N; Yakisich, JS; Iyer, AKV (2017). "Antitumor effects of naturally occurring cardiac glycosides convallatoxin and peruvoside on human ER+ and triple-negative breast cancers". Cell Death Discovery. 3: 17009. doi:10.1038/cddiscovery.2017.9. PMC   5327615 . PMID   28250972.
  22. ↑ Prassas, I; Diamandis, EP (2008). "Novel therapeutic applications of cardiac glycosides". Nature Reviews Drug Discovery. 7 (11): 926–35. doi:10.1038/nrd2682. PMID   18948999. S2CID   14459328.
  23. ↑ Amarelle, L; Lecuona, E (2018). "The Antiviral Effects of Na,K-ATPase Inhibition: A Minireview". International Journal of Molecular Sciences. 19 (8): 2154. doi: 10.3390/ijms19082154 . PMC   6121263 . PMID   30042322.
  24. 1 2 Cohen, CJ; Williams, JD; Opperman, TJ; Sanchez, R; Lurain, NS; Tortorella, D (2016). "Convallatoxin-Induced Reduction of Methionine Import Effectively Inhibits Human Cytomegalovirus Infection and Replication". Journal of Virology. 90 (23): 10715–10727. doi:10.1128/JVI.01050-16. PMC   5110156 . PMID   27654292.
  25. 1 2 Gozalpour, E; Greupink, R; Bilos, A; Verweij, V; van den Heuvel, JJ; Masereeuw, R; Russel, FG; Koenderink, JB (2014). "Convallatoxin: a new P-glycoprotein substrate". European Journal of Pharmacology. 744: 18–27. doi:10.1016/j.ejphar.2014.09.031. PMID   25264938.
  26. ↑ Gozalpour, E; Wilmer, MJ; Bilos, A; Masereeuw, R; Russel, FG; Koenderink, JB (2016). "Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays". Toxicology in Vitro. 32: 138–145. doi:10.1016/j.tiv.2015.12.009. PMID   26708294.
  27. ↑ Levrier, C; Kiremire, B; Guéritte, F; Litaudon, M (2012). "Toxicarioside M, a new cytotoxic 10β-hydroxy-19-nor-cardenolide from Antiaris toxicaria". Fitoterapia. 83 (4): 660–664. doi:10.1016/j.fitote.2012.02.001. PMID   22348979.
  28. ↑ Angarskaya, MA; Topchii, LY (1973). "Experimental results relating to the metabolism of the cardiac glycosides". Chemistry of Natural Compounds. 9 (5): 621–624. doi:10.1007/BF00564387. S2CID   4820710.
  29. ↑ Anderson, KE; Bergdahl, B; Bodem, G; Dengler, H; Dutta, S; Foerster, J; Greeff, K; Grosse-Brockhoff, F; Kriegelstein, J (2017). Cardiac Glycosides: Part II: Pharmacokinetics and Clinical Pharmacology. Springer Science & Business Media. pp. 73–74.
  30. ↑ Scheline, RR (1991). Handbook of Mammalian Metabolism of Plant Compounds. CRC Press.
  31. 1 2 Xu, J; Guo, Y; Sui, T; Wang, Q; Zhang, Y; Zhang, R; Wang, M; Guan, S; Wang, L (2017). "Molecular mechanisms of anti-oxidant and anti-aging effects induced by convallatoxin in Caenorhabditis elegans". Free Radical Research. 51 (5): 529–544. doi:10.1080/10715762.2017.1331037. PMID   28503972. S2CID   3830979.
  32. 1 2 Fitzgerald, KT (2010). "Lily toxicity in the cat". Topics in Companion Animal Medicine. 25 (4): 213–217. doi:10.1053/j.tcam.2010.09.006. PMID   21147474.
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