HaCaT cells undergo necroptosis when exposed to Lily of the Valley toxin [4].

In two mouse models of psoriasis, the toxin from lily of the valley exhibits antipsoriatic action [4].

Absorption, Distribution and Excretion
Fifteen cardiac glycosides labeled with 3H were injected intraluminally into ligated cat duodenal loops, and intestinal absorption was assessed. The concentrations of 3H in the portal venous circulation and bile were also monitored. Isolated, inverted rat jejunal specimens absorbed lily of the valley toxin via active transport. No correlation was observed between the amount of actively transported cardiac glycosides and tissue oxygen consumption. Digitalis derivatives (DLCs), such as digoxin and digitoxin, are currently used to treat heart failure and atrial fibrillation, but their therapeutic index is narrow. Drug interactions at the transporter protein level are a common cause of DLC toxicity. P-glycoprotein (P-gp, ABCB1) is the major transporter of digoxin, and its inhibitors affect the pharmacokinetics and distribution of digoxin in humans; however, the role of P-gp in the distribution of other digoxin derivatives (DLCs) remains unclear. This study investigated the transport of lily of the valley (DLC) by human P-gp using membrane vesicles derived from human embryonic kidney cells (HEK293) overexpressing P-gp. Quantitative analysis of the DLCs was performed using liquid chromatography-mass spectrometry (LC-MS). In the vesicle transport assay, lily of the valley toxin was identified as a substrate of P-gp (Km: 1.1 ± 0.2 mM). The transport effect of P-gp on lily of the valley toxin was confirmed in in vivo rat experiments; co-administration with the P-gp inhibitor elacridar led to increased lily of the valley toxin concentrations in the brain and renal cortex. To investigate the interaction between lily of the valley toxin and P-gp at the molecular level, we compared the effects of nine alanine mutants on the substrate N-methylquinidine (NMQ). Phe343 appeared to be more important for NMQ transport than for lily of the valley toxin transport, while Val982 was particularly associated with lily of the valley toxin transport. We identified lily of the valley toxin as a novel P-gp substrate and found that Val982 is a key amino acid involved in its transport. …

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Metabolism/Metabolites
During perfusion of isolated rat small intestine segments, sevigan and lily of the valley toxin were hydrolyzed to strophanthidin. Furthermore, the C10-aldehyde groups of these compounds were enzymatically reduced to seviganol, lily of the valley toxin alcohol, and strophanthidin alcohol. Besides the hydrolysis, the reduction of strophanthidin-like cardiac glycosides appears to be the most important biotransformation reaction in the rat small intestine.

Toxicity Summary
Identification and Uses: Conitoxin is a cardiac glycoside extracted from the flowers of Adonis vernalis, Convallaria majalis, Ornhogalum umbellatum, and Antiaris toxicaria. Its aglycone is conitoxin-formazin, and its glycosyl group is rhamnose. Conitoxin is used to treat acute and chronic congestive heart failure and paroxysmal tachycardia. Human Studies: Conitoxin has inhibitory and cytotoxic effects on human lung A549 cells. Nanomolar concentrations of conitoxin inhibit Na,K-ATPase in A549 cells. Animal Studies: Single intravenous injection of trace to lethal doses of conitoxin in rats or cats causes vascular disease of the heart, liver, and kidneys. Daily injections equivalent to 0.2 to 0.4 times the LD100 for 15 consecutive days cause malnutrition and promote infiltration and proliferation. The LD50 of lily of the valley toxin was 6.3 mg/kg after intravenous injection in mice. This glycoside caused tremors, convulsions, and limb paralysis, and affected respiration. The formulation caused cardiac dysfunction and transient coronary hypoperfusion. Researchers investigated the effects of single or repeated intraperitoneal injections of lily of the valley toxin on the histology of the heart, liver, kidneys, spleen, and lungs in mice, rats, and cats. A single injection dilated blood vessels in the heart, liver, and kidneys, causing hepatic hemorrhage and infiltrating proliferative effects in the heart and liver. Long-term injections resulted in more pronounced infiltrating proliferative effects than acute administration, and malnutrition-like changes were observed in the liver. Ecotoxicity studies showed that lily of the valley toxin (20 μM) significantly prolonged the lifespan of wild-type C. elegans by 16.3% via the daf-16 signaling pathway, but not the sir-2.1 signaling pathway, and improved its heat tolerance and resistance to paraquat-induced oxidative stress. Conch toxins also improve pharyngeal pumping function and motility in C. elegans, reduce lipofuscin accumulation and reactive oxygen species levels. These effects are attributed to their excitatory effects, free radical scavenging activity, and upregulation of stress-resistance-related proteins (such as SOD-3 and HSP-16.1). Furthermore, aging-related genes daf-16, sod-3, and ctel-2 also appear to be involved in the anti-stress effects of conch toxins. Conch toxins (CNTs) belong to the cardiac glycoside class of compounds. Cardiac glycosides are well-known Na+/K+-ATPase inhibitors, some of which are used to treat congestive heart failure and atrial arrhythmias. Recent studies have shown that cardiac glycosides have the potential as anticancer drugs. CNTs exhibit cytotoxic effects on various cancer cells and normal cell lines, and induce apoptosis by increasing the cleavage of caspase-3 and poly-ADP-ribose polymerase (PARP). Furthermore, dose- and time-dependent autophagy activity was detected in CNT-treated cells, and inhibition of the mammalian target of rapamycin (mTOR)/p70S6K signaling pathway was observed. Notably, CNTs inhibited the growth of human umbilical vein endothelial cells (HUVECs) and exerted anti-angiogenic activity in vitro and in vivo. (A15340)

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Non-human toxicity values
Mouse intraperitoneal LD50 10 mg/kg
Rat intravenous LD50 15 mg/kg
Mouse subcutaneous LD50 15 mg/kg
Mouse intravenous LD50 1 mg/kg
For more non-human toxicity values (complete data) for lily of the valley toxins (6 in total), please visit the HSDB record page.

[1]. Convallatoxin protects against dextran sulfate sodium-induced experimental colitis in mice by inhibiting NF-κB signaling through activation of PPARγ. Pharmacol Res. 2019 Sep;147:104355.

[2]. Convallatoxin: a new P-glycoprotein substrate. Eur J Pharmacol. 2014 Dec 5;744:18-27.

[3]. Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice. Sci Rep. 2019 Feb 20;9(1):2405.

[4]. Convallatoxin induces HaCaT cell necroptosis and ameliorates skin lesions in psoriasis-like mouse models. Biomed Pharmacother. 2020 Jan;121:109615.

Convallaria toxin is a cardiac glycoside composed of strophanthidin with a 6-deoxy-α-L-mannopyranosyl (L-rhamnosyl) group linked at the 3-position. It has vasodilatory effects and is also a metabolite. It is an α-L-rhamnoside, 19-oxosteroid, 14β-hydroxysteroid, 5β-hydroxysteroid, steroidal endose, and steroidal aldehyde. Its function is related to strophanthidin. Convallaria toxin has been reported in lily of the valley (Convallaria majalis), snow lotus (Saussurea stella), and other organisms with relevant data. Convallaria toxin is a glycoside extracted from lily of the valley (Convallaria majalis). Convallaria toxin can also be isolated from the bark of the poison tree (Antiaris toxicaria, A15340). Mechanism of Action The inhibitory activity of glycosides and related compounds on Na+-K+-ATPase was determined and correlated with their cardiotonic activity in cats. Results showed that the active site of Na+-K+-ATPase consists of two parts; one part binds the cardiotonic steroid compound to its receptor and orients the molecule relative to the other part (i.e., the catalytic moiety). The relationship between these results and the cardiotonic activity of strophanthidin alcohol analogues is discussed. Therapeutic Uses Vasodilator /EXPL THER/ lily of the valley toxin improved myocardial diastole and increased systolic heart rate and contractility in the early stages of canine cor pulmonale (chronic pneumonia). In an experimental model of cor pulmonale with pulmonary hypertension, positive inotropic effects were accompanied by increased right ventricular load and further increases in pulmonary artery blood pressure. /EXPL THER/ lily of the valley toxin had no effect on left ventricular hemodynamics in intact dogs, but decreased right ventricular pressure and increased dp/dt max and dp/dt minimum. In animals undergoing pulmonary trunk stenosis surgery, elevated right ventricular pressure and dp/dt max, decreased left ventricular end-diastolic pressure, and elevated left ventricular dp/dt max were observed. Administration of lily of the valley toxin one month post-stenosis did not improve cardiac hemodynamics. Cytomegalovirus (CMV) is a ubiquitous human pathogen that increases morbidity and mortality in immunocompromised individuals. Currently approved FDA treatments for CMV infection target specific viruses, but they have significant adverse side effects, including nephrotoxicity and hematologic toxicity. Therefore, there is an urgent need for safer and more effective CMV treatments. We used a high-throughput screening method to identify the cardiac glycoside lily of the valley toxin as a compound that can effectively inhibit CMV infection. We evaluated key structural elements of its anti-CMV activity using a series of cardiac glycoside variants through experimental and computer simulation methods. Antiviral, toxicological, and pharmacodynamic analyses of different cardiac glycoside variants showed that its inhibitory mechanism is the reduction of methionine input, thereby decreasing early gene translation, without significant toxicity. Furthermore, lily of the valley toxin significantly reduced the proliferation of clinical CMV strains, indicating that its mechanism of action is an effective strategy for blocking CMV transmission. Our study revealed the mechanism of action and structural elements of lily of the valley toxin, which are crucial for effectively inhibiting cytomegalovirus (CMV) infection by targeting the expression of early genes. Importance: Cytomegalovirus is a highly prevalent virus that can cause severe illness in certain populations. Currently approved FDA therapies target the same stage of the viral life cycle and induce toxicity and drug resistance. We have discovered a novel cell-targeted antiviral drug—lily of the valley toxin—that inhibits CMV infection by reducing viral protein synthesis. At cell-tolerant low doses, lily of the valley toxin inhibited primary CMV isolates, including strains resistant to the CMV drug ganciclovir. In addition to discovering lily of the valley toxin as a novel antiviral drug, limiting mRNA translation also had a significant impact on CMV infection and proliferation.

C29H42O10

550.64

550.278

508-75-8

441852

White to off-white solid powder

1.41 g/cm3

757.3ºC at 760 mmHg

235-242ºC

247.1ºC

1.622

0.75

5

10

4

39

1050

13

C[C@H]1[C@@H]([C@H]([C@H]([C@@H](O1)O[C@H]2CC[C@@]3([C@H]4CC[C@@]5([C@H](CC[C@@]5([C@@H]4CC[C@@]3(C2)O)O)C6=CC(=O)OC6)C)C=O)O)O)O

HULMNSIAKWANQO-JQKSAQOKSA-N

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

(3S,5S,8R,9S,10S,13R,14S,17R)-5,14-dihydroxy-13-methyl-17-(5-oxo-2H-furan-3-yl)-3-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxy-2,3,4,6,7,8,9,11,12,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-10-carbaldehyde

Korglykon Corglykon Convallatoxin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~90.80 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (4.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)