Bufotalin

Last updated
Bufotalin
Bufotalin.svg
Names
IUPAC name
3β,14-Dihydroxy-5β-bufa-20,22-dienolid-16β-yl acetate
Systematic IUPAC name
(1R,2S,3aS,3bR,5aR,7S,9aS,9bS,11aR)-3a,7-Dihydroxy-9a,11a-dimethyl-1-(1-oxo-1H-oxan-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-2-yl acetate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C26H36O6/c1-15(27)32-21-13-26(30)20-6-5-17-12-18(28)8-10-24(17,2)19(20)9-11-25(26,3)23(21)16-4-7-22(29)31-14-16/h4,7,14,17-21,23,28,30H,5-6,8-13H2,1-3H3/t17-,18+,19+,20-,21+,23+,24+,25-,26+/m1/s1 Yes check.svgY
    Key: VOZHMAYHYHEWBW-NVOOAVKYSA-N Yes check.svgY
  • InChI=1/C26H36O6/c1-15(27)32-21-13-26(30)20-6-5-17-12-18(28)8-10-24(17,2)19(20)9-11-25(26,3)23(21)16-4-7-22(29)31-14-16/h4,7,14,17-21,23,28,30H,5-6,8-13H2,1-3H3/t17-,18+,19+,20-,21+,23+,24+,25-,26+/m1/s1
    Key: VOZHMAYHYHEWBW-NVOOAVKYBX
  • 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
Properties
C26H36O6
Molar mass 444.568 g·mol−1
Appearancecrystalline solid
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Toxic
Lethal dose or concentration (LD, LC):
4.13 mg·kg−1 (mouse, IV)

0.4 mg·kg−1 (mouse, SC)
0.136 mg·kg−1 (cat, IV) [1]

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Bufotalin is a cardiotoxic bufanolide steroid, cardiac glycoside analogue, secreted by a number of toad species. [2] [3] Bufotalin can be extracted from the skin parotoid glands of several types of toad.

Contents

Sources

Rhinella marina (Cane toad), Rhaebo guttatus (Smooth-sided toad), Bufo melanostictus (Asian toad), and Bufo bufo (common European toad) are sources of bufotalin. [2] [3] [4]

Traditional medicine

Bufotalin is part of Ch'an Su, a traditional Chinese medicine used for cancer. It is also known as Venenum Bufonis or senso (Japanese). [5]

Toxicity

Specifically, in cats the lethal median dose is 0.13 mg/kg. [1] and in dogs is 0.36 mg/kg (intravenous). [6]

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, cholestyramine, a bile salt, might help. [6] Recent animal studies have shown that taurine restores cardiac functions. [7]

Symptomatic measures include lignocaine, atropine and phenytoin for cardiac toxicity and intravenous potassium compounds to correct hyperkalaemia from its effect on the Na+/K+ ATPase pump. [6]

Pharmacology and mechanism of action

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. [8] It also increases cancer cell's susceptibility to apoptosis via TNF-α signalling by the BH3 interacting domain death agonist and STAT proteins. [9]

Bufotalin induces apoptosis in vitro in human hepatocellular carcinoma Hep 3B cells and might involve caspases and apoptosis inducing factor (AIF). [10] The use 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.

Pharmacokinetics

The mechanism of the biotransformation of bufotalin is still unknown. Researches found, that bufotalin is biotransformed into at least 5 different compounds. [11]

The five known biotransformation products of bufotalin. Biotransformation products of bufotalin.JPG
The five known biotransformation products of bufotalin.

Chemical properties

If bufotalin is esterified with suberyl arginine, the bufotalin-like steroid bufotoxin is obtained. [12]

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses between 50 and 70 billion cells each day due to apoptosis. For an average human child between eight and fourteen years old, each day the approximate lost is 20 to 30 billion cells.

<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.

<span class="mw-page-title-main">Common toad</span> Species of amphibian

The common toad, European toad, or in Anglophone parts of Europe, simply the toad, is a frog found throughout most of Europe, in the western part of North Asia, and in a small portion of Northwest Africa. It is one of a group of closely related animals that are descended from a common ancestral line of toads and which form a species complex. The toad is an inconspicuous animal as it usually lies hidden during the day. It becomes active at dusk and spends the night hunting for the invertebrates on which it feeds. It moves with a slow, ungainly walk or short jumps, and has greyish-brown skin covered with wart-like lumps.

<span class="mw-page-title-main">Bufotoxin</span> Class of chemical compounds

Bufotoxins are a family of toxic steroid lactones or substituted tryptamines of which some are toxic. They occur in the parotoid glands, skin, and poison of many toads and other amphibians, and in some plants and mushrooms. The exact composition varies greatly with the specific source of the toxin. It can contain 5-MeO-DMT, bufagins, bufalin, bufotalin, bufotenin, bufothionine, dehydrobufotenine, epinephrine, norepinephrine, and serotonin. Some authors have also used the term bufotoxin to describe the conjugate of a bufagin with suberylarginine.

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">Cardiotoxin III</span>

Cardiotoxin III is a sixty amino-acid polypeptide toxin from the Taiwan Cobra Naja atra. CTX III is highly basic and hydrophobic protein. It is an example of a group of snake cardio/cytotoxins, which are made up of shorter snake venom three-finger toxins. Over 50 different cytotoxin polypeptides have been isolated and sequenced from venom samples. The difference in the CTX functionality may be due to the relatively small difference in the polypeptide's structure, allowing different CTXs to induce lysis in different cell types. The CTX III molecule contains multiple binding sites and is cytolytic for myocardial cells and human leukemic T cells.

<i>Deinagkistrodon</i> Genus of snakes

Deinagkistrodon is a monotypic genus created for the venomous pit viper species, Deinagkistrodon acutus, which is endemic to Southeast Asia. No subspecies are currently recognized.

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

Monocrotophos is an organophosphate insecticide. It is acutely toxic to birds and humans, so it has been banned in the U.S., the E.U., India and many other countries.

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

Levobupivacaine (rINN) is a local anaesthetic drug indicated for minor and major surgical anaesthesia and pain management. It is a long-acting amide-type local anaesthetic that blocks nerve impulses by inhibiting sodium ion influx into the nerve cells. Levobupivacaine is the S-enantiomer of racemic bupivacaine and therefore similar in pharmacological effects. The drug typically starts taking effect within 15 minutes and can last up to 16 hours depending on factors such as site of administration and dosage.

<span class="mw-page-title-main">Survivin</span> Mammalian protein

Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the BIRC5 gene.

<span class="mw-page-title-main">Smooth-sided toad</span> Species of amphibian

The smooth-sided toad or spotted toad, formerly known as Bufo guttatus, is a species of toad in the family Bufonidae. It is found in the Amazonian Bolivia, Brazil, Colombia, Ecuador, Peru, and Venezuela, as well as the Guianas. Specimens from southern Peru, Bolivia, and Brazil might represent Rhaebo ecuadorensis described in 2012.

<i>Rhinella icterica</i> Species of amphibian

Rhinella icterica is a species of toad in the family Bufonidae that is found in northeastern Argentina, southern Brazil, and eastern Paraguay. "Cururu" is its indigenous name and refers to the male advertisement call that is a melodious tremolo. "Cururu toad", without the specifier "yellow", is a common name used for a few other closely related species.

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

Marinobufagenin (marinobufagin) is a cardiotonic bufadienolide steroid. It can be found in the plasma and urine of human subjects with myocardial infarction, kidney failure, and heart failure. It is also secreted by the toad Bufo rubescens and other related species such as Bufo marinus. It is a vasoconstrictor with effects similar to digitalis.

<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">Bufothionine</span> Chemical compound

Bufothionine is a sulfur-containing compound which is present in the bufotoxins secreted by the parotoid gland of certain toads of the genera Bufo and Chaunus. This specific compound can be found in the skin of certain species of toad such as the Asiatic Toad, Chaunus arunco, Chaunus crucifer, Chaunus spinulosus, and Chaunus arenarum.

<span class="mw-page-title-main">FL3 (flavagline)</span> Chemical compound

FL3 is a synthetic flavagline that displays potent anticancer and cardioprotectant activities. This compound induces the death of cancer cells by an original mechanism that involves the apoptosis-inducing factor and caspase 12, suggesting that it may improve the efficacy of cancer chemotherapies. It was also shown that FL3 may enhance the efficacy of one of the most widely used anticancer agents, doxorubicin, and alleviate its main adverse effect, cardiac damage.

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

Bufalin is a cardiotonic steroid toxin originally isolated from Chinese toad venom, which is a component of some traditional Chinese medicines.

<span class="mw-page-title-main">Dicycloplatin</span>

Dicycloplatin is a chemotherapy medication used to treat a number of cancers which includes the non-small-cell lung carcinoma and prostate cancer.

<i>Rhaebo</i> Genus of amphibians

Rhaebo is a genus of true toads, family Bufonidae, from Central and South America. They are distributed from Honduras to northern South America including the Amazonian lowlands. Common name Cope toads has been suggested for them.

References

  1. 1 2 "Datasheet: Bufotalin sc-202509" Santa Cruz Biotechnology, Inc. http://datasheets.scbt.com/sc-202509.pdf
  2. 1 2 Kwan, T; Paiusco, AD; Kohl, L (September 1992). "Digitalis toxicity caused by toad venom" (PDF). Chest. 102 (3): 949–50. doi:10.1378/chest.102.3.949. PMID   1325343. Archived from the original (PDF) on 2014-10-11. Retrieved 2014-03-05.
  3. 1 2 Jan, SL; Chen, FL; Hung, DZ; Chi, CS (November–December 1997). "Intoxication after ingestion of toad soup: report of two cases". Zhonghua Minguo Xiao Er Ke Yi Xue Hui Za Zhi. 38 (6): 477–80. PMID   9473822.
  4. Ferreira, PM; Lima, DJ; Debiasi, BW; Soares, BM; Machado Kda, C; Noronha Jda, C; Rodrigues Dde, J; Sinhorin, AP; Pessoa, C; Vieira GM, Jr (September 2013). "Antiproliferative activity of Rhinella marina and Rhaebo guttatus venom extracts from Southern Amazon". Toxicon. 72: 43–51. doi: 10.1016/j.toxicon.2013.06.009 . PMID   23796725.
  5. Zhang, DM; Liu, JS; Tang, MK; Yiu, A; Cao, HH; Jiang, L; Chan, JY; Tian, HY; Fung, KP; Ye, WC (October 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:10.1016/j.ejphar.2012.06.045. PMID   22841670.
  6. 1 2 3 Spoerke, DG (November 1986). "Toad Toxins".
  7. Ma, Hongyue; Jiang, J; Zhang, J; Zhou, J; Ding, A; Lv, G; Xu, H; You, F; Zhan, Z; Duan, J (January 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. doi:10.3109/15376516.2011.583295. PMID   22150009. S2CID   7187045.
  8. Yu, CL; Hou, HM (25 December 2010). "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. PMID   21302038. S2CID   27185931.
  9. Waiwut, P; Inujima, A; Inoue, H; Saiki, I; Sakurai, H (January 2012). "Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent pathways" (PDF). International Journal of Oncology. 40 (1): 203–8. doi: 10.3892/ijo.2011.1182 . PMID   21887462.
  10. Su, CL; Lin, TY; Lin, CN; Won, SJ (14 January 2009). "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. PMID   19055367.
  11. Zhang, X; Ye, M; Dong, YH; Hu, HB; Tao, SJ; Yin, J; Guo, DA (October 2011). "Biotransformation of bufadienolides by cell suspension cultures of Saussurea involucrata". Phytochemistry. 72 (14–15): 1779–85. Bibcode:2011PChem..72.1779Z. doi:10.1016/j.phytochem.2011.05.004. PMID   21636103.
  12. Müller-Schwarze, D (2006). Chemical ecology of vertebrates. Cambridge: Cambridge University Press. p. 255. ISBN   978-0521363778.