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Arenobufagin is a
cardiotoxic Cardiotoxicity is the occurrence of heart dysfunction as electric or muscle damage, resulting in heart toxicity. The heart becomes weaker and is not as efficient in pumping blood. Cardiotoxicity may be caused by chemotherapy (a usual example is the ...
bufanolide Bufanolide is a C24 steroid and, indirectly, a parent structure of bufadienolide. Its derivatives was found in ''Bufo'' and ''Scilla'', as an aglycone of cardiac glycosides and is usually toxic Toxicity is the degree to which a chemical su ...
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
secreted by the Argentine
toad Toad is a common name for certain frogs, especially of the family Bufonidae, that are characterized by dry, leathery skin, short legs, and large bumps covering the parotoid glands. A distinction between frogs and toads is not made in scient ...
''
Bufo arenarum ''Rhinella arenarum'' is a species of toad in the family Bufonidae that is found in southern Brazil and Uruguay; can also occur in Paraguay. It is also found in Argentina from the Chubut Province northward, Bolivia , image_flag ...
''. It has effects similar to
digitalis ''Digitalis'' ( or ) is a genus of about 20 species of herbaceous perennial plants, shrubs, and biennials, commonly called foxgloves. ''Digitalis'' is native to Europe, western Asia, and northwestern Africa. The flowers are tubular in sh ...
, blocking the Na+/K+ pump in heart tissue.


Sources

The compound arenobufagin is one of the major components of
toad venom Bufotoxins are a family of toxic steroid lactones or substituted tryptamines of which some may or may not be toxic. They occur in the parotoid glands, skin, and poison of many toads ( genus '' Bufo'') and other amphibians, and in some plants a ...
. It is derived from the dried skin of giant toads, such as ''
Bufo gargarizans The Asiatic toad or Chusan Island toad (''Bufo gargarizans'') is a species of toad endemic to East Asia. The species was previously classified as ''Bufo bufo gargarizans'', a subspecies of the common toad. Distribution and habitat It is comm ...
'' and ''
Bufo melanostictus Suhneider ''Bufo'' is a genus of true toads in the amphibian family Bufonidae. As traditionally defined, it was a wastebasket genus containing a large number of toads from much of the world, but following taxonomic reviews most of these have been moved ...
''. Arenobufagin is specifically secreted by ''
Rhinella arenarum ''Rhinella arenarum'' is a species of toad in the family Bufonidae that is found in southern Brazil and Uruguay; can also occur in Paraguay. It is also found in Argentina from the Chubut Province northward, Bolivia , image_flag ...
'', which is found in South America. The venom of these toad species contains about 1.75% of arenobufagin. The other major part of the venom consists mostly of similar looking
bufagin 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 ...
s, which are all toxic
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
s. 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 Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of act ...
in the treatment of
liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
. Also, it is reported to have a simulative effect upon the
heart The heart is a muscular organ found in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon diox ...
. 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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
cells. In fact, this compound showed the most potent antitumor activity of fifteen bufadionolides isolated from Chan’su.


Function in medicine

As already mentioned, arenobufagin has been widely used in
traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logica ...
(TCM) to tackle down
carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
, since it inhibits cell growth in several
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
cells. It is one of the central active ingredients of toad venom for treatment. This happens both in purified form or in combination with other ingredients, which are mostly
herb In general use, herbs are a widely distributed and widespread group of plants, excluding vegetables and other plants consumed for macronutrients, with savory or aromatic properties that are used for flavoring and garnishing food, for medicina ...
al components. Toad venom is in fact still used in clinical practice of in TCM to treat
hepatocellular carcinoma Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in th ...
(HCC). 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.


Intake

Under normal circumstances, arenobufagin is a
solid Solid is one of the four fundamental states of matter (the others being liquid, gas, and plasma). The molecules in a solid are closely packed together and contain the least amount of kinetic energy. A solid is characterized by structura ...
. In
Chinese traditional medicine Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of act ...
, it in ingested either orally or topically, for example to the skin. Little is known about its
toxicokinetics Toxicokinetics (often abbreviated as 'TK') is the description of both what rate a chemical will enter the body and what occurs to excrete and metabolize the compound once it is in the body. Relation to Pharmacokinetics It is an application of pha ...
.


Toxicodynamics

Arenobufagin is believed to play a role in the regulation of the transport of water and electrolytes across
cell membranes The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (th ...
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 Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. O ...
. 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 A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...
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 Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves li ...
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 Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
, which were discovered in experiment with
cancer cell lines Cancer cells are cells that divide continually, forming solid tumors or flooding the blood with abnormal cells. Cell division is a normal process used by the body for growth and repair. A parent cell divides to form two daughter cells, and these d ...
. 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 The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
to mitochondria was also found to be increased. In addition to these effects, arenobufagin also induces morphological changes in
organelles In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
, blebbing of plasma membrane, shrinkage of
nuclear membrane The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material. The nuclear envelope consists of two lipid bilayer membra ...
and
chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important ...
condensation. These observation also indicate the occurrence of apoptosis. Last but not least, specific cleavage of poly (
ADP-ribose Adenosine diphosphate ribose (ADPR) is an ester molecule formed into chains by the enzyme poly ADP ribose polymerase. ADPR is created from cyclic ADP-ribose (cADPR) by the CD38 enzyme using nicotinamide adenine dinucleotide (NAD+) as a cofactor. ...
) 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 An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, in ...
and
lysosomes A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane ...
, 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 P62 may refer to: Naval vessels * , a submarine of the Royal Navy * , a corvette of the Indian Navy * , an offshore patrol vessel of the Irish Naval Service * P-62 ''Explorer'', a fictional icebreaker in the 2019 Indian film ''War'' Other uses * ...
/
SQSTM1 Sequestosome-1 is a protein that in humans is encoded by the ''SQSTM1'' gene. Also known as the ubiquitin-binding protein p62, it is an autophagosome cargo protein that targets other proteins that bind to it for selective autophagy. By interacti ...
, all
proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respondi ...
which induce autophagy. Blockers of autophagy increase the
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating ...
effect of arenobufagin. Addition of 3-MA increases the proportion of cells in which there in enlarged PARP cleavage and limited
caspase-9 Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
and
caspase-3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also ...
cleavage. This indicates that autophagy pathways protect the cell against apoptosis by arenobufagin. It was hypothesized that arenobufagin may inhibit the
PI3K Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
/
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tr ...
pathway in controlling cell death and
differentiation Differentiation may refer to: Business * Differentiation (economics), the process of making a product different from other similar products * Product differentiation, in marketing * Differentiated service, a service that varies with the identity ...
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 The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''MTOR'' gene. ...
-protein, which is involved in apoptosis as well as in autophagy.


Detoxification

The biotransformation of arenobufagin by ''
Alternaria alternata ''Alternaria alternata'' is a fungus which has been recorded causing leaf spot and other diseases on over 380 host species of plant. It is an opportunistic pathogen on numerous hosts causing leaf spots, rots and blights on many plant parts. It ...
'' leads to the following three metabolites: 3-oxo-arenobufagin (1a), ψ-bufarenogin (1b), 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. :


Similar forms

Arenobufagin is a derivative of the so-called
bufadienolide Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolide glycosides (bufadienolides that contain structural groups derived from sugars). Thes ...
s, where it also has a steroid structure. A characteristic of bufadienolides is that they all contain two double bonds in the
lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...
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 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in th ...
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 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 co ...
. Cardiac glycosides are natural compounds found in plants which cause inactivation of the
sodium potassium pump Sodium is a chemical element with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable is ...
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. arenobufagin.png, Structure of arenobufagin Proscillaridin.png, Structure of a cardiac glycoside,
proscillaridin Proscillaridin is a cardiac glycoside, a kind of drug that can be used in the treatment of congestive heart failure and cardiac arrhythmia (irregular heartbeat). It is of the bufanolide type and can be obtained from plants of the genus '' Scilla' ...


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 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in th ...
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 A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
.


See also

*
Bufagin 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 ...
*
Bufadienolide Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides, including many in the form of bufadienolide glycosides (bufadienolides that contain structural groups derived from sugars). Thes ...
*
Cinobufagin 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. Isolation and purification Cinobufagin, as well as other bu ...
* Gamabufagin *
Marinobufagin Marinobufagenin (marinobufagin) is a cardiotonic bufadienolide steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as i ...
* Quercicobufagin * Regularobufagin * Vallicepobufagin * Viridibufagin *
Digitalis ''Digitalis'' ( or ) is a genus of about 20 species of herbaceous perennial plants, shrubs, and biennials, commonly called foxgloves. ''Digitalis'' is native to Europe, western Asia, and northwestern Africa. The flowers are tubular in sh ...


References

{{Cardiac glycosides Vertebrate toxins Bufanolides Polyols