Bufotalin
| Bufotalin | |
|---|---|
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| IUPAC name ((3S,5R,10S,13R,14S,16S,17R)-3,14-dihydroxy-10,13-dimethyl-17-(6-oxopyran-3-yl)-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-16-yl)acetate | |
| Other names Bufotalin | |
| Identifiers | |
| CAS number | 471-95-4  |
| PubChem | 10119 |
| ChemSpider | 16735710 |
| ChEMBL | CHEMBL463064 |
| Jmol-3D images | {{#if:CC(=O)O[C@H]1C[C@@]2(C3CC[C@@H]4C[C@H](CC[C@@]4(C3CC[C@@]2([C@H]1C5=COC(=O)C=C5)C)C)O)O|Image 1 |
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| Properties | |
| Molecular formula | C26H36O6 |
| Molar mass | 444.56 g mol−1 |
| Appearance | crystalline solid |
| Hazards | |
| Main hazards | Toxic |
| LD50 | 4,13 mg·kg−1 (mouse, intravenous)
0,4 mg·kg−1 (mouse, subcutaneous) 0,136 mg·kg−1 (cat, intravenous)[1] |
(verify) (what is: / ?)Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa) | |
| Infobox references | |
Bufotalin is a cardiotoxic bufanolide steroid, cardiac glycoside analogue, secreted by the Common European toad (Bufo bufo) and other related toads such as Bufo melanostictus.[2][3]
Sources
Toads
Toads possess two types of alveolar glands in epidermis of their skin: mucous and granular glands. The granular glands are known to produce acrid poisons or toxins. In case of Bufo bufo and related toads such as the Asian Common Toad it produces bufotalin.
Other sources
Bufadienolides or compounds with similar structures, like bufotalin, are not only found in toads but also in plants, fireflies (Photinus sp.), Snakes (Rhabdophis sp.) and mammals.
Chemical properties
Bufalin, Bufogenin, Bufotalin, Cinobufagin, Marinobufagin, Resibufagin are some of the most important bufadienolides. Major bufadienolides isolated from skin secretions of Bufo sp.Biogenic amines present in toad-secretions include serotonin (5-hydroxytryplanime), histamine, bradykinin etc. Bufadienolide is regarded as derivative of steroids with two double-bonds present in bufanolide side-chain such that it's known as bufotoxin when in combined-state with nitrogenous compounds like arginine and bufogenin when in free-state. Toad skin glands actually secrete a compound called bufonin, which is a weaker poison but as soon as it comes in contact with air it gets oxidized to a bufadienolide called Bufotalin [C26H26O6] which imparts a milky appearance to the toad secretions. This molecule is a steroid that has an additional six ring group attached. The additional group is aromatic. Bufotalin acts like the drug digitalis. Bufotalin is a crystalline solid that reacts like an weak acid, it is soluble in chloroform and alcohol, but not in ether and also not well mixed with water. If Bufotalin is esterized with suberyl arginine the bufotalin like steroid bufotoxin is obtained. [4]
Use & Research
Bufotalin is part of the traditional Chinese ch'an su, it is also known as Venenum Bufonis[5] or senso (Japanese). Bufotalin can be extracted from the skin parotid glands of the Common European toad (Bufo bufo).It is especially of research interest, as it is one of Chan su’s most potent active compounds, that at the same time as it is not that toxic, as the other bufanolide substances.[5]
Bufotalin research is mostly done in the field of biochemistry, and it is used for cancer therapies & research on celullar dynamics.
Medical use
Bufotalin is part of Ch'an Su, a traditional Chinese pharmacy and its used for cancer therapies. Researchers recently reveald that bufotalin induces apoptosis in human hepatocellular carcinoma Hep 3B cells and might involve caspases and AIF(Apoptosis inducing factor), that's why it could be used in terms of cancer treatment.[6] The applyment of bufotalin as a cancer treating compound is still in the experimental phase. It also arrests cell cycle at G(2)/M, by up and down regulation of several enzymes .[7]
Toxicity
Bufotalin is found to inhibit myocardial Na+/K+ ATPase activity by that increasing myocardial contractile force. Furthermore bufotalin was not found to affect the heart-rate with those changes in myocardial Na+/K+ ATPase activity.[8] Bufotalin which structure looks like the one of digitalin and digitoxin, shows effects on cardiovascular system as well. After a single intravenous injection, bufotalin gets quickly distributed and eliminated from the blood plasma with a half-time of 28.6 minutes and a MRT of 14.7 min. After 30 minutes after an administration of bufotalin, the concentrations within the brain and lungs are significantly higher than those in blood and other tissues.[9]
Range
It just sufficient the skin of a toad to induce toxic symptoms in human and in the others animal species. The acute toxicity LD50/LC50 (lethal dose, 50 percent kill) of Bufotalin is 300 µg/kg in mammal(intravenous) and in rodent-mouse 400 µg/kg(subcutaneous).[10] Specifically, in cats is 0.13 mg/kg.[1] and in dogs is 0.36 mg/kg (intravenous).[11]
Biotransformation
The mechanism of the biotransformation of bufotalin is still unknown. Researches found, that bufotalin is biotransformed into at least 5 different compounds.[12]
Cases of intoxication
A bufotalin intoxication after ingestion of toad is rare. Even though an intoxication is rare it results in severe morbidity and high mortality. There are two reported cases of intoxication involving a 15-month-old boy and a 20-month-old girl, who were fed with a cooked toad (Bufo melanostictus) soup. In the case of the boy, it is reported, that he expired ventricular fibrillation. The girl showed varying degrees of AV block along with congestive heart failure, which was completely resolved after intensive care.
Treatment of poisoning
One of the most important steps in the treatment of a bufotalin treatment is to stop the uptake of the compound into the blood system. This can be done by washing contaminated skin sections profoundly or in case of a gastric poisoning by gastric lavage.
As described in ‘Toxicity’ bufotalin inhibits myocardial Na+/K+ ATPase activity, thereby causing cardiac dysrhythmia and abnormal rates. Knowing this it is advisable to monitor those functions continuously using an EKG. As there is no antidote against bufotalin all occurring symptoms need to be treated separately or if possible in combination with others. To increase the clearance theoretically, due to the similarities with digitoxin, an oral administration of 6 grams of cholestyramine every 6 hours might help.[11]
Recent research on guinea pigs showed, that a dose about 150 mg/kg of taurine restores cardiac functions.[13]
One of the dysrhythmia coming along with bufotalin intoxication is an atrioventricular block (AV block). An AV block is a dysrhythmia of the atria and ventricles of the heart due to interference in conduction between those two. An AV block can be treated by intravenous injection of atropine (Adults: 0,6 mg/dose; Children: 10-30 µg/dose up to 0,4 mg/dose) or phenytoin (Adults: 25 mg/dose; Children: 0,5-1,0 mg/dose; in an interval of 1–2 hours). If a patient does not respond to the treatment a transvenous pacemaker should be considered.[11]
A patient suffering from a sinoatrial block (SA block) can be helped by intravenous administration of atropine (Adults: 0,6 mg/dose; Children: 10-30 µg/dose up to 0,4 mg/dose).[11]
Another cardiac effect that can be caused by bufotalin is a ventricular dysrhythmia, which can be managed by an intravenous loading dose of 15 mg/kg up to 1,0 gram. A rate of 0,5 mg/kg per minute may not be exceeded. An intravenous maintenance dose of 2 mg/kg should be administered every 12 hours as needed for adults and every 8 hours as needed for children.[11]
Treatment of ventricular tachyarrhythmias and premature ventricular contractions can be achieved by lidocaine treatment. Adults should be given a bolus of 0,70 -1,4 mg/kg at a rate of 25 to 50 mg/minute. If the wanted effect is not obtained a second bolus may be given 5 minutes after the first intravenous injection. A maximum administration of 200 –300 mg per hour should not be exceeded. After the desired effect is obtained an infusion of lidocaine at a rate of 0,014 up to 0,057 mg/kg/min. might be given. Children should be treated with a bolus of 1 mg/kg and an infusion of 3 µg/kg/min. may be used.[11]
Though the myocardial Na+/K+ ATPase activity is inhibited, hyperkalemia is another effect observed during bufotalin intoxication. At a potassium level greater than 6,5 mEq/L 0,2 units/kg of regular insulin and 200 to 400 mg/kg glucose should be injected intravenous in a 25% dextrose/water solution. Along with an intravenous injection of sodium bicarbonate. The dose of this injection should be 1,0 mEq/kg up to maximum of 44 mEq per dose. The serum potassium level should be lowered up to 12 hours. After that the therapy might be repeated.[11]
References
- ↑ 1.0 1.1 "Datasheet: Bufotalin sc-202509" Santa Cruz Biotechnology, Inc.http://datasheets.scbt.com/sc-202509.pdf
- ↑ Kwan T, Paiusco AD, Kohl L. Digitalis toxicity caused by toad venom. Chest. 1992 Sep;102(3):949-50. PMID 1325343
- ↑ Jan SL, Chen FL, Hung DZ, Chi CS. Intoxication after ingestion of toad soup: report of two cases. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. 1997 Nov-Dec;38(6):477-80. PMID 9473822
- ↑ Dietland Müller-Schwarze: Chemical Ecology of Vertebrates. Cambridge University Press, Cambridge 2006, ISBN 978-0521363778, P. 255.
- ↑ 5.0 5.1 Zhang, D.-M., et al. (2012). "Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis." European Journal of Pharmacology 692(1–3): 19-28.
- ↑ Su, C.-L., Lin, T.-Y., Lin, C.-N., & Won, S.-J. (2008). Involvement of Caspases and Apoptosis-Inducing Factor in Bufotalin-Induced Apoptosis of Hep 3B Cells. Journal of Agricultural and Food Chemistry, 57(1), 55-61. doi: 10.1021/jf802769g
- ↑ Zhang, D.-M., Liu, J.-S., Tang, M.-K., Yiu, A., Cao, H.-h., Jiang, L., . . . Ye, W.-C. (2012). Bufotalin from Venenum Bufonis inhibits growth of multidrug resistant HepG2 cells through G2/M cell cycle arrest and apoptosis. European Journal of Pharmacology, 692(1–3), 19-28. doi: http://dx.doi.org/10.1016/j.ejphar.2012.06.045
- ↑ A.D. Garg, R. Hippargi, A.N. Gandhare: Toad skin-secretions: Potent source of pharmacologically and therapeutically significant compounds. The Internet Journal of Pharmacology. 2008 Volume 5 Number 2. DOI: 10.5580/18b6 - See more at: http://archive.ispub.com/journal/the-internet-journal-of-pharmacology/volume-5-number-2/toad-skin-secretions-potent-source-of-pharmacologically-and-therapeutically-significant-compounds.html#sthash.cKvye0Gg.dpuf
- ↑ Yu, C.-l., & Hou, H.-m. (2011). Plasma pharmacokinetics and tissue distribution of bufotalin in mice following single-bolus injection and constant-rate infusion of bufotalin solution. European Journal of Drug Metabolism and Pharmacokinetics, 35(3-4), 115-121. doi: 10.1007/s13318-010-0017-6
- ↑ Bufotalin acute toxicity data - See more at http://www.drugfuture.com/toxic/q34-q565.html
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "Toad Toxins" David G. Spoerke http://www.erowid.org/animals/toads/toads_health1.shtml.
- ↑ Zhang, X., et al. (2011). "Biotransformation of bufadienolides by cell suspension cultures of Saussurea involucrata." Phytochemistry 72(14–15): 1779-1785.
- ↑ Ma, H., et al. (2012). "Protective effect of taurine on cardiotoxicity of the bufadienolides derived from toad (Bufo bufo gargarizans Canto) venom in guinea-pigs in vivo and in vitro." Toxicology Mechanisms and Methods 22(1): 1-8.
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