Calotropin is a
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
cardenolide
A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycoside ...
found in plants in the family ''
Asclepiadoideae
The Asclepiadoideae are a subfamily of plants in the family Apocynaceae. Formerly, they were treated as a separate family under the name Asclepiadaceae, e.g. by APG II, and known as the milkweed family.
They form a group of perennial herbs, twi ...
''. In extreme cases, calotropin poisoning can cause
respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gre ...
and
cardiac
The heart is a muscular organ 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 dioxide to t ...
failure. Accidental poisoning is common in livestock who have ingested
milkweed
''Asclepias'' is a genus of herbaceous, perennial, flowering plants known as milkweeds, named for their latex, a milky substance containing cardiac glycosides termed cardenolides, exuded where cells are damaged. Most species are toxic to humans ...
. Calotropin is commonly stored as a
defense mechanism
In psychoanalytic theory, a defence mechanism (American English: defense mechanism), is an unconscious psychological operation that functions to protect a person from anxiety-producing thoughts and feelings related to internal conflicts and o ...
by
insect
Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three ...
s that eat milkweeds as their main food source.
Chemistry
Calotropin is a
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...
compound and is classified as a cardenolide-type
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 c ...
. These molecules are related to
steroids, and have a similar carbon backbone. Calotropin, like calactin, calotoxin, and uscharin, is based on
calotropagenin, the precursor to these molecules. They have similar activity and are often found together in plants of the genus ''
Calotropis
''Calotropis'' is a genus of flowering plants in the family Apocynaceae, first described as a genus in 1810. It is native to southern Asia and North Africa.
They are commonly known as milkweeds because of the latex they produce. ''Calotropis'' ...
''.
Biosynthesis
It is thought that the
biosynthesis of calotropin is similar to that of
digitoxin
Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, w ...
, another cardenolide. Digitoxin is more established as a medicine for
cardiac insufficiency, and therefore the biosynthesis has been further studied. However, it is believed that many cardenolides are synthesized in
plant
Plants are predominantly photosynthetic eukaryotes of the kingdom Plantae. Historically, the plant kingdom encompassed all living things that were not animals, and included algae and fungi; however, all current definitions of Plantae exclu ...
s by a similar process, but this process is not yet well understood. The sterol precursor for this process is similar to precursors for
steroidal alkaloids. Two suggested pathways, the
pregnane
Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally allop ...
pathway and norcholanic acid pathway are possible for the conversion of the sterol precursor to
digitoxigenin
Digitoxigenin, a cardenolide, is the aglycone of digitoxin.
Digitoxigenin can be used to prepare actodigin.
In Lednicer's book on steroids, it is made from deoxycholic acid
Deoxycholic acid is a bile acid. Deoxycholic acid is one of the se ...
, the precursor to digitoxin. Both the pregnane and norcholanic acid pathways use
progesterone 5β-reductases, the P5βR and P5βR2 respectively. In the pregnane pathway, a plant analog of the mitochondrial
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
(CYP11A in humans), is thought to catalyze the conversion of
pregnenolone
Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/ metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
to progesterone. Progesterone is further processed by P5βR to 5β-Pregnane-3,20-dione, and then to digitoxigenin. Less is known about the norcholanic acid pathway. At this point the similarities between digitoxin and calotropin end. Calotropogenin may be produced by the same process as digitoxigenin, however the mechanism for production of calotropin and digitoxin from these
genins diverges. It is not well studied how calotropin is produced from its calotropogenin precursor.
Toxicity
Mechanism of action
Cardenolides such as calotropin inhibit the
sodium-potassium pump, Na
+/K
+-ATPase. This
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
is responsible for
active transport
In cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...
of sodium and potassium ions across the cell membrane. This process also helps to regulate the
resting potential A relatively static membrane potential which is usually referred to as the ground value for trans-membrane voltage.
The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as opp ...
and cell volume. Inhibition of this enzyme in cardiac tissue is proposed as the receptor for calotropin and cardiac glycosides in general, and this is responsible for the toxic effects.
Inhibition of the Na
+/K
+-ATPase causes an increase of sodium inside the cell, and by the action of the
sodium-calcium exchanger
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by al ...
(NCX) also raises the calcium concentration. Calotropin has a more noticeable effect on the
myocardium than it does on skeletal muscles, as these cells have more active NCX proteins. This can allow for higher
cardiac output by the cardiac muscles, but can also lead to
arrhythmia, which is aggravated by the charge buildup that develops when Na
+/K
+-ATPase is inhibited.
Symptoms and bioactivity
Poisoning can cause a variety of unpleasant symptoms including abdominal pain, bloating, diarrhoea, muscle tremors,
seizures
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
, and death.
Death can be caused by
hemorrhages
Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, ...
in the lungs, respiratory failure, or cardiac failure. Symptoms can begin as early as two hours after ingestion, and may persist for hours or days.
Ingestion is not always lethal, and plants in the genus ''Calotropis'' have long been used as a folk remedy in India.
[Upadhyay RK. Ethnomedicinal, pharmaceutical and pesticidal uses of Calotropis procera (Aiton) (Family: Asclepiadaceae). Int J Green Pharm 2014;8:135-46.]
Natural sources
Plants
Calotropin is primarily generated by plants in the ''Asclepiadoideae'' family, and can be obtained or isolated from plant extracts of ''Calotropis gigantea'' and ''
Calotropis procera
''Calotropis procera'' is a species of flowering plant in the family Apocynaceae that is native to North Africa, Pakistan, tropical Africa, Western Asia, South Asia, and Indochina. The green fruits contain a toxic milky sap that is extremely b ...
''. Asclepiadoideae plants are commonly regarded as poisonous, and are common around the world. Calotropin is found in the
latex
Latex is an emulsion (stable dispersion) of polymer microparticles in water. Latexes are found in nature, but synthetic latexes are common as well.
In nature, latex is found as a milky fluid found in 10% of all flowering plants (angiosperms ...
,
leaves, and root bark.
Ingestion of these plants is toxic to
mammals, and can be life-threatening.
Insects
Monarch butterflies
The monarch butterfly or simply monarch (''Danaus plexippus'') is a milkweed butterfly (subfamily Danainae) in the family Nymphalidae. Other common names, depending on region, include milkweed, common tiger, wanderer, and black-veined brown. ...
are one of many insects that feed on milkweed plants. These butterflies feed on the
North American milkweed (''
Asclepias
''Asclepias'' is a genus of herbaceous, perennial, flowering plants known as milkweeds, named for their latex, a milky substance containing cardiac glycosides termed cardenolides, exuded where cells are damaged. Most species are toxic to humans ...
)'' plants. These milkweeds are related to the
India
India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
n and
North Africa
North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in ...
n milkweeds (''
Calotropis
''Calotropis'' is a genus of flowering plants in the family Apocynaceae, first described as a genus in 1810. It is native to southern Asia and North Africa.
They are commonly known as milkweeds because of the latex they produce. ''Calotropis'' ...
''), which are consumed by the North African grasshopper ''
Poekilocerus bufonis''.
These insects have adapted to the toxicity of the milkweed, are capable of safely sequestering
cardenolide
A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycoside ...
s from the milkweed in glands or tissues during their
early stages of development.
The insects primarily retain calotropin and calactin (a
configurational isomer), even though other cardenolides exist in the plant latex and leaves. These poisons, while not harmful to the insect, make it unpalatable to
bird
Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweig ...
s and mammals, and therefore serve as a defense mechanism. Monarch butterflies also store several
volatile pyrazine
Pyrazine is a heterocyclic aromatic organic compound with the chemical formula C4H4N2. It is a symmetrical molecule with point group D2h. Pyrazine is less basic than pyridine, pyridazine and pyrimidine. It is a ''"deliquescent crystal or wax-li ...
s, which give off an odor, which is a
warning signal
Aposematism is the advertising by an animal to potential predators that it is not worth attacking or eating. This unprofitability may consist of any defences which make the prey difficult to kill and eat, such as toxicity, venom, foul taste or ...
to predators to avoid the insect.
''P. bufonis'' is capable of utilizing calotropin in its defensive spray.
See also
* ''
Calotropis gigantea
''Calotropis gigantea'', the crown flower, is a species of ''Calotropis'' native to Cambodia, Vietnam, Bangladesh, Indonesia, Malaysia, Thailand, Sri Lanka, India, China, Pakistan, and Nepal.
It is a large shrub growing to tall. It has clus ...
''
* ''
Calotropis procera
''Calotropis procera'' is a species of flowering plant in the family Apocynaceae that is native to North Africa, Pakistan, tropical Africa, Western Asia, South Asia, and Indochina. The green fruits contain a toxic milky sap that is extremely b ...
''
* ''
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 shap ...
''
*
Milkweed
''Asclepias'' is a genus of herbaceous, perennial, flowering plants known as milkweeds, named for their latex, a milky substance containing cardiac glycosides termed cardenolides, exuded where cells are damaged. Most species are toxic to humans ...
References
{{Reflist
Cardenolides