| |
| Names | |
|---|---|
| IUPAC name
Card-20(22)-enolide, 14-hydroxy-19-oxo-3,2-((tetrahydro-3,4-dihydroxy-6-methyl-2H-pyran-2,3-diyl)bis(oxy))-, (2alpha(2S,4S,6R),3beta,5alpha)-
| |
| Other names
Pecilocerin A, Pekilocerin A
| |
| Identifiers | |
PubChem CID
|
|
| UNII | |
| Properties | |
| C29H40O9 | |
| Molar mass | 532.630 g·mol−1 |
| Melting point | 223 °C |
| Hazards | |
| Lethal dose or concentration (LD, LC): | |
LD50 (median dose)
|
9800 μg/kg (mouse)[1] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
For Calotropin (published page)
editNOTE: The calotropin information has been published as its own unique page. The information published by me as found below.
Calotropin is a fairly toxic cardenolide found in plants in the family Asclepiadoideae. Calotropin, sourced from Calotropis Gigantea, has been used as a folk medicine in India and has been recently researched as a cancer drug and contraceptive. 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.
Chemistry
editCalotropin is a toxic compound and is classified as a cardenolide-type cardiac glycoside. These molecules are related to steroids, and have a similar carbon backbone. Calotropin, like calactin, calotoxin, and uscharin, is based on calotropagenin, the precursor to these molecules. They seem to have similar activity and are often found together in plants of the Calotropis genus[2].
Biosynthesis
editIt is thought that the biosynthesis of calotropin is similar to that of digitoxin, another cardenolide. Digitoxin is more established as a medicine for cardiac insufficiency, and therefore the biosynthesis has been further studied. However, it is believed that many cardenolides are synthesized in plants by a similar process, but this process is not yet well understood. The sterol precursor for this process is similar to precursors for steroidal alkaloids. Two suggested pathways, the pregnane pathway and norcholanic acid pathway are possible for the conversion of the sterol precursor to digitoxigenin, the precursor to digitoxin. Both the pregnane and norcholanic acid pathways use progesterone 5β-reductases, the P5βR and P5βR2 respectively. In the pregnane pathway, a plant analog of the mitochondrial cytochrome P450 (CYP11A in humans), is thought to catalyze the conversion of pregnenolone to progesterone. Progesterone is further processed by P5βR to 5β-Pregnane-3,20-dione, and then to digitoxigenin. Less is known about the norcholanic acid pathway. At this point the similarities between digitoxin and calotropin end. Calotropogenin may be produced by the same process as digitoxigenin, however the mechanism for production of calotropin and digitoxin from these genins diverges. It is not well studied how calotropin is produced from its calotropogenin precursor.[3][4]
Toxicity
edit
Mechanism Of Action
editCardenolides like calotropin inhibit the sodium-potassium pump, Na+/K+-ATPase. This enzyme is responsible for active transport of sodium and potassium ions across the cell membrane. This process also helps to regulate the resting potential and cell volume. Inhibition of this enzyme in cardiac tissue is proposed as the receptor for calotropin and cardiac glycosides in general, and this is responsible for the toxic effects.[3][5] Inhibition of the Na+/K+-ATPase causes an increase of sodium inside the cell, and by the action of the sodium-calcium exchanger (NCX) also raises the calcuim concentration. Calotropin has a more noticeable effect on the myocardium than it does on skeletal muscles, as these cells have more active NCX proteins.[6] This can allow for higher cardiac output by the cardiac muscles, but can also lead to arrhythmia, which is aggravated by the charge buildup that develops when Na+/K+-ATPase is inhibited.[7]
Symptoms and Bioactivity
editPoisoning can cause a variety of unpleasant symptoms including abdominal pain, bloating, diarrhea, muscle tremors, seizures, and death.[8] Death can be caused by hemorrhages in the lungs, respiratory failure, or cardiac failure. Symptoms can begin as early as two hours after ingestion, and may persist for hours or days.[5] Ingestion is not always lethal, and plants in the Calotropis genus have long been used as a folk remedy in India.[9]
Natural Sources
edit
Plants
editCalotropin is primarily generated by plants in the Asclepiadoideae family, and can be obtained or isolated from plant extracts of Calotropis Gigantea and Calotropis Procera. Asclepiadoideae plants are commonly regarded as poisonous, and are common around the world. Calotropin is found in the latex,[9] leaves, and root bark.[2] Ingestion of these plants is toxic to mammals, and can be life-threatening.[8]
Insects
editMonarch butterflies are one of many insects that feed on milkweed plants.[10] These butterflies feed on the North American milkweed (Asclepias) plants. These milkweeds are related to the Indian and North African milkweeds (Calotropis), which are consumed by the North African grasshopper Poekilocerus bufonis.[11] These insects have adapted to the toxicity of the milkweed, are capable of safely sequestering cardenolides from the milkweed in glands or tissues during their early stages of development.[12] The insects primarily retain calotropin and calactin (a configurational isomer), even though other cardenolides exist in the plant latex and leaves. These poisons, while not harmful to the insect, make it unpalatable to birds and mammals, and therefore serve as a defense mechanism. Monarch butterflies also store several volatile pyrazines, which give off an odor, which is a warning signal to predators to avoid the insect.[11] P. bufonis is capable of utilizing calotropin in it's defensive spray.[3]
Medical Uses
editCalotropis plants have been used in Indian folk medicine for a long time. It was used, within non-lethal limits, for its digitalis-like effect on the heart, as a substitute for ipecac, as an analgesic, as an anti-cancer medication, and a treatment for many other illnesses.[13][9] Like many bioactive plants, it has been used in an attempt to cure a wide variety of ailments. However, the truth of these claims has only recently been investigated, both with plant extracts and purified chemicals.
Cancer Treatement
editPhytochemicals have recently gained interest in the quest to develop more effective cancer treatments, and have shown abilities to decrease a cell's resistance to apoptosis. Recently, calotropin, reported to have anti-cancer properties, has been shown to be cytotoxic to some cancer cells. Calotropin was tested on human leukemia cells, and an investigation of the mechanism of calotropin-induced apoptosis showed that it may be an important molecule in enhancing the efficacy of existing chemotherapies. Calotropin-induced apoptosis studies found that calotrpoin aids the activation of caspase enzymes by degrading anti-apoptotic proteins in the cells and therefore leading to better activation of caspases in leukemia cells.[14]
Birth Control
editTypical forms of chemical birth control are hormonal, with most female birth control containing estrogen and/or progestin. A number of chemical male birth control methods have been investigated, but most are still experimental. In general, hormonal birth control methods can lead to side effects, leading to research into non-horomonal methods. It has been shown that temporary infertility can be achieved, without hormone level changes, by inhibiting Katanin p60 ATPase-containing subunit A-like 1 protein (KATNAL1). Inhibition of KATNAL1 prevents sperm maturation, and calotropin is identified as an ideal candidate for binding with KATNAL1. Calotropin is still an experimental method, but given its good bioavailability, no mutagenicity, and good binding efficiency with KATNAL1, it is a promising candidate for future study.[15]
For Calotropis Gigantea (published edits to existing page)
editNOTE: The Calotropis gigantea information has been published to the Calotropis gigantea page. It was inserted into the uses section, but for efficiency my additions are below.
Use as an Arrow Poison
editMany plant and animal extracts have been used as arrow poisons all over the world. In many cases, the poison was applied to the arrow or spear to aid the hunting of prey. Alkaloids are among the most powerful plant poisons, and extracts of Strychnos species are commonly used. Other arrow poisons are commonly cardiac glycosides, which can be found in digitalis, but most of these arrow poisons are derived from plants in the Apocynaceae family.[16] This family includes Calotropis gigantea and the more potent Calotropis procera. The latex of these plants has been used in Africa as an arrow poison. Apocynaceae species often contain a mixture of cardiac glycosides, including calactin, uscharin, calotoxin, and calotropin.[2] These poisons work by inhibiting the sodium-potassium pump, and this effect is especially potent in the cardiac tissues.[3] The cardiac effects can be applied for heart medication, and digitalis has been used as such. However, excessive doses can cause arrhythmia, which can lead to death.[7]
Medical Uses
editGiven the potent bioactivity of calotropin, calotropis gigantea has been used as a folk medicine in India for many years, and has been reported to have a variety of uses. In Ayurveda, Indian practitioners have used the root and leaf of C. procera in asthma and shortness of breath and the bark in liver and spleen diseases. The plant is reported as effective in treating skin, digestive, respiratory, circulatory and neurological disorders and was used to treat fevers, elephantiasis, nausea, vomiting, and diarrhea. The milky juice of Calotropis procera was used against arthritis, cancer, and as an antidote for snake bite.[9] However, these reports are of folk uses and more research is needed to confirm the clinical usefulness of the leaves, latex, and bark. Recent studies have displayed use of calotropin as a contraceptive[15] and as a promising cancer medication[14]. In one study of the cancer-fighting properties of Calotropis gigantea, DCM extracts were demonstrated to be strongly cytotoxic against non-small cell lung carcinoma (A549), colon carcinoma (HCT 116), and hepatocellular carcinoma (Hep G2). These extracts show promise as cancer medications and warrant further clinical research.[17]
References
edit- ^ "Haz-Map Category Details". hazmap.nlm.nih.gov. Retrieved 2018-04-25.
- ^ a b c 1949-, Daniel, M. (Mammen) (2006). Medicinal plants : chemistry and properties. Enfield, NH: Science Publishers. ISBN 1578083958. OCLC 61456768.
{{cite book}}:|last=has numeric name (help)CS1 maint: multiple names: authors list (link) - ^ a b c d Agrawal, Anurag A.; Petschenka, Georg; Bingham, Robin A.; Weber, Marjorie G.; Rasmann, Sergio (2012-01-31). "Toxic cardenolides: chemical ecology and coevolution of specialized plant-herbivore interactions". New Phytologist. 194 (1): 28–45. doi:10.1111/j.1469-8137.2011.04049.x. ISSN 0028-646X. PMID 22292897.
- ^ Bauer, Peter; Munkert, Jennifer; Brydziun, Margareta; Burda, Edyta; Müller-Uri, Frieder; Gröger, Harald; Muller, Yves A.; Kreis, Wolfgang (2010). "Highly conserved progesterone 5β-reductase genes (P5βR) from 5β-cardenolide-free and 5β-cardenolide-producing angiosperms". Phytochemistry. 71 (13): 1495–1505. doi:10.1016/j.phytochem.2010.06.004. ISSN 0031-9422. PMID 20598327.
- ^ a b Pubchem. "Calotropin". pubchem.ncbi.nlm.nih.gov. Retrieved 2018-04-26.
- ^ "NA+/K+-ATPase and inhibitors (Digoxin) - Pharmacorama". www.pharmacorama.com. Retrieved 2018-04-30.
- ^ a b Hoyer, Kirsten; Song, Yejia; Wang, Desuo; Phan, Dillon; Balschi, James; Ingwall, Joanne S.; Belardinelli, Luiz; Shryock, John C. (2011-05-01). "Reducing the Late Sodium Current Improves Cardiac Function during Sodium Pump Inhibition by Ouabain". Journal of Pharmacology and Experimental Therapeutics. 337 (2): 513–523. doi:10.1124/jpet.110.176776. PMID 21325441. S2CID 16793407.
- ^ a b "Guide to Poisonous Plants – College of Veterinary Medicine and Biomedical Sciences – Colorado State University". csuvth.colostate.edu. Retrieved 2018-04-25.
- ^ a b c d Upadhyay RK. Ethnomedicinal, pharmaceutical and pesticidal uses of Calotropis procera (Aiton) (Family: Asclepiadaceae). Int J Green Pharm 2014;8:135-46.
- ^ Giller, Geoffrey (2015-11-04). "Butterflies Weaponize Milkweed Toxins". The Scientist. Retrieved 2018-04-25.
- ^ a b David), Morgan, E. David (Eric (2010). Biosynthesis in insects. Royal Society of Chemistry (Great Britain) (Advanced ed.). Cambridge: Royal Society of Chemistry. ISBN 9781847558084. OCLC 664322798.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ Comprehensive natural products chemistry. Barton, Derek H. R., 1918-1998., Nakanishi, Kōji, 1925, Meth-Cohn, Otto., 中西, 香爾, (1925- ) (1st ed.). Amsterdam: Elsevier. 1999. ISBN 008042709X. OCLC 38765050.
{{cite book}}: CS1 maint: others (link) - ^ Seema Mahesh Hadimani, Anitha M. G. A Review on Toxicity of Calotropis (Arka) and Management. International Journal of Ayurveda and Pharma Research. 2015;3(4):1-5.
- ^ a b Wang, Shih-Chung; Lu, Mei-Chin; Chen, Hsiu-Lin; Tseng, Hsing-I; Ke, Yu-Yuan; Wu, Yang-Chang; Yang, Pei-Yu (2009). "Cytotoxicity of calotropin is through caspase activation and downregulation of anti-apoptotic proteins in K562 cells". Cell Biology International. 33 (12): 1230–1236. doi:10.1016/j.cellbi.2009.08.013. ISSN 1065-6995. PMID 19732845. S2CID 29139887.
- ^ a b Sarma, Kishore; Roychoudhury, Shubhadeep; Bora, Sudipta; Dehury, Budheswar; Parida, Pratap; Das, Saurav; Das, Robin; Dohutia, Chandrajit; Nath, Sangeeta (2017-03-23). "Molecular Modeling and Dynamics Simulation Analysis of KATNAL1 for Identification of Novel Inhibitor of Sperm Maturation". Combinatorial Chemistry & High Throughput Screening. 20 (1): 82–92. doi:10.2174/1386207320666170116120104. ISSN 1386-2073. PMID 28093975.
- ^ Philippe, Geneviève; Angenot, Luc (2005). "Recent developments in the field of arrow and dart poisons". Journal of Ethnopharmacology. 100 (1–2): 85–91. doi:10.1016/j.jep.2005.05.022. ISSN 0378-8741. PMID 15993556.
- ^ Jacinto, S.D.; Chun, E.A.C.; Montuno, A.S.; Shen, C.C.; Espineli, D.L.; Ragasa, C.Y. (2011). "Cytotoxic Cardenolide and Sterols from Calotropis gigantea". Natural Product Communications. 6 (6): 803–806. doi:10.1177/1934578X1100600614. PMID 21815415. S2CID 40801911.