Arenobufagin

Last updated
Arenobufagin
Arenobufagin.png
Names
IUPAC name
5-[(3S,5R,10S,11S,13R,14S,17R)-3,11,14-trihydroxy-10,13-dimethyl-12-oxo-2,3,4,5,6,7,8,9,11,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-17-yl]pyran-2-one
Other names
Arenobufagin
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C24H32O6/c1-22-9-7-15(25)11-14(22)4-5-17-19(22)20(27)21(28)23(2)16(8-10-24(17,23)29)13-3-6-18(26)30-12-13/h3,6,12,14-17,19-20,25,27,29H,4-5,7-11H2,1-2H3/t14-,15+,16-,17-,19-,20+,22+,23+,24+/m1/s1 Yes check.svgY
    Key: JGDCRWYOMWSTFC-AZGSIFHYSA-N Yes check.svgY
  • C[C@]12CC[C@@H](C[C@H]1CCC3C2[C@@H](C(=O)[C@]4([C@@]3(CC[C@@H]4C5=COC(=O)C=C5)O)C)O)O
Properties
C24H32O6
Molar mass 416.514 g·mol−1
Appearanceliquid
Density 1.4±0.1 g/cm3
Boiling point 637.2±55.0 °C at 760 mmHg
Vapor pressure 0.0±4.3 mmHg at 25 °C
1.622
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Cardiotoxic
GHS labelling:
GHS-pictogram-skull.svg
Danger
Flash point 219.3±25.0 °C
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 ?)

Arenobufagin is a cardiotoxic bufanolide steroid secreted by the Argentine toad Bufo arenarum . [1] It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue. [2]

Contents

Sources

The compound arenobufagin is one of the major components of toad venom. It is derived from the dried skin of giant toads, such as Bufo gargarizans and Bufo melanostictus Suhneider . Arenobufagin is specifically secreted by Rhinella arenarum , which is found in South America. The venom of these toad species contains about 1.75% of arenobufagin. [3] The other major part of the venom consists mostly of similar looking bufagins, which are all toxic steroids. Toads produce their venom when they are scared, injured, or provoked, as a defense mechanism against their predators.

History

Arenobufagin is a component of a certain toad venom which goes by the name of Chan’su. For centuries, this venom has been used in Chinese traditional medicine in the treatment of liver cancer. Also, it is reported to have a simulative effect upon the heart. It is derived from the dried skin secretions of giant toads. In a 2013 study, it was shown that arenobufagin inhibits the growth of certain liver tumor cells. In fact, this compound showed the most potent antitumor activity of fifteen bufadionolides isolated from Chan’su. [4]

Function in medicine

As already mentioned, arenobufagin has been widely used in traditional Chinese medicine (TCM) to tackle down carcinogenesis, since it inhibits cell growth in several cancer cells. It is one of the central active ingredients of toad venom for treatment. [5] This happens both in purified form or in combination with other ingredients, which are mostly herbal components. Toad venom is in fact still used in clinical practice of in TCM to treat hepatocellular carcinoma (HCC). [6] So far there is still little known about the anti-angiogenic properties of Arenobufagin. One studie shows that Arenobufagin inhibits VEGF-induced endothial cell tube formation. [7]

Intake

Under normal circumstances, arenobufagin is a solid. In Chinese traditional medicine, it in ingested either orally or topically, for example to the skin. Little is known about its toxicokinetics.

Toxicodynamics

Proposed model of arenobufagin interactions ArenobufaginInteractions.jpg
Proposed model of arenobufagin interactions

Arenobufagin is believed to play a role in the regulation of the transport of water and electrolytes across cell membranes under physiological conditions. Experimental results show that Arenobufagin inhibits the sodium-potassium adenosine triphosphatase (Na+/K+-ATPase) . It is one of the most potent blockers that are known to science, along with ouabain. It has been suggested that uncharged and non-polar amino acids may participate in the binding of arenobufagin to the extracellular surface of the ATPase. If this is the case, the steroid nucleus of arenobufagin probably also contributes to the binding. Furthermore, the presence of a sugar group in ouabain and the absence of one in arenobufagin suggests that it may me more lipophilic that ouabain and as such form a more stable complex with the Na+-K+ pump.

Besides its effects on the Na+-K+ pump, arenobufagin also has some other effects on cells, which were discovered in experiment with cancer cell lines. It causes apoptosis by tempering with mitochondria. In cells treated with it, a decreasing mitochondrial potential was detected (in a dose-dependent manner), as well as a high Bax/Bcl-2 ratio, which is associated with apoptosis, or programmed cell death. Bax translocation from cytosol to mitochondria was also found to be increased. In addition to these effects, arenobufagin also induces morphological changes in organelles, blebbing of plasma membrane, shrinkage of nuclear membrane and chromatin condensation. These observation also indicate the occurrence of apoptosis. Last but not least, specific cleavage of poly (ADP-ribose) polymerase (PARP) and a decrease in pro-caspase9 and 3 were also induced by arenobufagin treatment. PARP is mainly involved in cell repair and programmed cell death. After treatment with arenobufagin, some cells make more autophagosomes and lysosomes, whereas other cells undergo apoptosis. Arenobufagin also leads to increased expression of LC3-II, Biclin1(initial vesicle formation), Atg5 (elongation and completion), Atg9, Atg16L1 and p62/SQSTM1, all proteins which induce autophagy. Blockers of autophagy increase the cytotoxic effect of arenobufagin. Addition of 3-MA increases the proportion of cells in which there in enlarged PARP cleavage and limited caspase-9 and caspase-3 cleavage. This indicates that autophagy pathways protect the cell against apoptosis by arenobufagin. It was hypothesized that arenobufagin may inhibit the PI3K/Akt pathway in controlling cell death and differentiation in response to external stimuli. It was found that arenobufagin inhibited the proteins Akt, PDK1 and PI3K, whereas it stimulated the PHEN-protein. It does this by altering the degree of phosphorylation. All these proteins are involved in the PI3/Akt pathway. Further down the pathway, arenobufagin indirectly inhibits the mTOR-protein, which is involved in apoptosis as well as in autophagy. [8]

Detoxification

The biotransformation of arenobufagin by Alternaria alternata leads to the following three metabolites: 3-oxo-arenobufagin (1a), ψ-bufarenogin (1b), [9] and 3- oxo- ψ-bufarenogin (1c). The biotransformation processes consists of a main reaction whereas the dehydrogenation of the 3-hydroxyl group takes place. This process is followed by isomerization. [10]

DetoxArenobufagin.jpg

Similar forms

Arenobufagin is a derivative of the so-called bufadienolides, where it also has a steroid structure. A characteristic of bufadienolides is that they all contain two double bonds in the lactone ring.

Symptoms

Circulatory system

Arenobufagin works like Cardiac glycosides. It inhibits the sodium-potassium pump because it stabilises the E2-P transition state, in which the pump is inactive. Second membrane transporter NCX is responsible for 3Na/Ca transport, if the Na-K-Pump does not function correctly the Ca concentration inside the cell will rise and this will cause heart failure. However, in experiments concerning the anti-cancer effects of arenobufagin in mice, no negative effects where found.

Digestive system

Arenobufagin has shown to cause appoptose in hepatocellular carcinoma cells in mice, although this method is not used to cure hepatocellular carcinoma in modern human medicine.

Structure-activity relationships

There is a rather large homology in structure between arenobufagin and cardiac glycosides. Cardiac glycosides are natural compounds found in plants which cause inactivation of the sodium potassium pump like arenobufagin. The specific steroidic structure binds to the pump in a way it inhibits the process of pumping potassium into the cell and sodium out of the cell. The exact way of binding to the Na-K-Pump is not yet documented.

Toxicity

Acute toxicity

Although a low dosis of arenobufagin can be used as a medicine of heart rate problems, a high dose can lead to acute heart problems and even death. Arenobufagin is also toxic for hepatocellular carcinoma cells, which is a positive result for the body.

Chronic exposure

Toxicity because of chronic exposure was not clearly documented thus far. However it is discussed that the chronic exposure to this compound can cause the development of tumors.

See also

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 include 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 and milkweed 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">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

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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.

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">Cardiotoxin III</span>

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

Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolide glycosides. These are a type of cardiac glycoside, the other being the cardenolide glycosides. Both bufadienolides and their glycosides are toxic; specifically, they can cause an atrioventricular block, bradycardia, ventricular tachycardia, and possibly lethal cardiac arrest.

<span class="mw-page-title-main">Zinc transporter SLC39A7</span> Protein found in humans

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References

  1. ↑ Garraffo HM, Gros EG. Biosynthesis of bufadienolides in toads. VI. Experiments with [1,2-3H]cholesterol, [21-14C]coprostanol, and 5 beta-[21-14 °C]pregnanolone in the toad Bufo arenarum. Steroids. 1986 Sep-Oct;48(3-4):251-7. PMID   3127947
  2. ↑ Cruz J dos S, Matsuda H. Arenobufagin, a compound in toad venom, blocks Na(+)-K+ pump current in cardiac myocytes. European Journal of Pharmacology. 1993 Aug 3;239(1-3):223-6. PMID   8223897
  3. ↑ Li, Manmei; Wu, Shuai; Liu, Zhong; Zhang, Wei; Xu, Jing; Wang, Ying; Liu, Junshan; Zhang, Dongmei; Tian, Haiyan; Li, Yaolan; Ye, Wencai (2012). "Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGF-mediated angiogenesis through suppression of VEGFR-2 signaling pathway". Biochemical Pharmacology. 83 (9): 1251–1260. doi:10.1016/j.bcp.2012.01.023. PMID   22305746.
  4. ↑ Zhang, D. M., et al. (2013). "Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway." Carcinogenesis 34(6): 1331-1342.
  5. ↑ Li M, Wu S, Liu Z, Zhang W, Xu J, Wang Y, Liu J, Zhang D, Tian H, Li Y, Ye W. (2012). “Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGFmediated angiogenesis through suppression of VEGFR-2 signaling pathway.” Biochemical Pharmacology. 83, 1251–1260
  6. ↑ Tang, J. et al. (2008) “Research progress on clinical application of venenum bufonis preparation as antineoplastic drug.” China Pharmaceuticals, 17, 15-16.
  7. ↑ Li M, Wu S, Liu Z, Zhang W, Xu J, Wang Y, Liu J, Zhang D, Tian H, Li Y, Ye W. (2012). “Arenobufagin, a bufadienolide compound from toad venom, inhibits VEGFmediated angiogenesis through suppression of VEGFR-2 signaling pathway.” Biochemical Pharmacology. 83, 1251–1260
  8. ↑ Zhang, D. M., et al. (2013). "Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway." Carcinogenesis 34(6): 1331-1342.
  9. ↑ Liu, Yanfang; Feng, Jiatao; Xiao, Yuansheng; Guo, Zhimou; Zhang, Jing; Xue, Xingya; Ding, Jin; Zhang, Xiuli; Liang, Xinmiao (2010). "Purification of active bufadienolides from toad skin by preparative reversed‐phase liquid chromatography coupled with hydrophilic interaction chromatography". Journal of Separation Science. 33 (10): 1487–1494. doi:10.1002/jssc.200900848. PMID   20432230.
  10. ↑ Zhang, Xing; Ye, Min; Dong, Yin-Hui; Hu, Hong-Bo; Tao, Si-Jia; Chen, Guang-Tong; Yin, Jun; Guo, De-An (2011). "Biotransformation of arenobufagin and cinobufotalin by Alternaria alternata". Biocatalysis and Biotransformation. 29 (2–3): 96–101. doi:10.3109/10242422.2011.578248. S2CID   84624677.
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