Bufotalin
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Bufotalin 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 th ...
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 a ...
,
cardiac glycoside 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 ...
analogue, secreted by a number of toad species. Bufotalin can be extracted from the skin
parotoid gland The parotoid gland (alternatively, paratoid gland) is an external skin gland on the back, neck, and shoulder of toads and some frogs and salamanders. It can secrete a number of milky alkaloid substances (depending on the species) known collective ...
s of several types of toad.


Sources

''
Rhinella marina The cane toad (''Rhinella marina''), also known as the giant neotropical toad or marine toad, is a large, terrestrial true toad native to South and mainland Central America, but which has been introduced to various islands throughout Oceania ...
'' (Cane toad), ''
Rhaebo guttatus The smooth-sided toad or spotted toad (''Rhaebo guttatus''), 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 th ...
'' (Smooth-sided toad), '' Bufo melanostictus'' (Asian toad), and ''
Bufo bufo The common toad, European toad, or in Anglophone parts of Europe, simply the toad (''Bufo bufo'', from Latin ''bufo'' "toad"), is a frog found throughout most of Europe (with the exception of Ireland, Iceland, and some Mediterranean islands), in ...
'' (common European toad) are sources of bufotalin.


Traditional medicine

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


Toxicity

Specifically, in cats the lethal median dose is 0.13 mg/kg."Datasheet: Bufotalin sc-202509" ''Santa Cruz Biotechnology, Inc.''http://datasheets.scbt.com/sc-202509.pdf and in dogs is 0.36 mg/kg (intravenous). 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 Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, wh ...
, a
bile salt Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Prima ...
, might help. Recent animal studies have shown that taurine restores cardiac functions. Symptomatic measures include
lignocaine Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the amino amide type. It is also used to treat ventricular tachycardia. When used for local anaesthesia or in nerve blocks, lidoca ...
,
atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...
and
phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. The intr ...
for cardiac toxicity and intravenous potassium compounds to correct
hyperkalaemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...
from its effect on the Na+/K+ ATPase pump.


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. It also increases cancer cell's susceptibility to apoptosis via
TNF-α Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
signalling by the
BH3 interacting domain death agonist The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1 ...
and
STAT protein STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...
s. Bufotalin induces apoptosis ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'' in human hepatocellular carcinoma Hep 3B cells and might involve caspases and apoptosis inducing factor (AIF). 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.


Chemical properties

If bufotalin is
esterified In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides are fa ...
with suberyl arginine, the bufotalin-like steroid
bufotoxin Bufotoxins are a family of toxic steroid lactones or substituted Substituted tryptamine, 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, an ...
is obtained.


References

{{Cardiac glycosides Vertebrate toxins Bufanolides Acetate esters