Biliverdin
Encyclopedia
Biliverdin is a green tetrapyrrolic bile
pigment
, and is a product of heme
catabolism
. It is the pigment responsible for a greenish color sometimes seen in bruise
s.
in erythrocytes. Macrophage
s break down senescent erythrocytes and break the heme down into biliverdin, which normally rapidly reduces to free bilirubin
. Biliverdin is seen briefly in some bruises as a green color. Its breakdown into bilirubin in bruises, leads to a yellowish color.
is caused by the accumulation of biliverdin or bilirubin (or both) in the circulatory system and tissues. Jaundiced skin and sclera
(whites of the eyes) are characteristic of liver failure.
Bile pigments such as biliverdin naturally possess significant anti-mutagenic and antioxidant properties and therefore fulfill a useful physiological function. Biliverdin and bilirubin have been shown to be potent scavengers of peroxyl radicals. They have also been shown to inhibit the effects of polycyclic aromatic hydrocarbon
s, heterocyclic amines, and oxidants — all of which are mutagens. Studies have even found that people with higher concentrations levels of bilirubin and biliverdin in their bodies have a lower frequency of cancer
and cardiovascular disease
.
A 1996 study by McPhee et al. suggested that biliverdin — as well as many other tetrapyrrolic pigments — may function as an HIV-1 protease inhibitor
. Of the fifteen compounds tested, biliverdin was one of the most active. In vitro
experiments showed that biliverdin and bilirubin competitively inhibited HIV-1 proteases at low micromolar concentrations, reducing viral infectivity
. However, when tested in cell culture with micromolar concentrations, it was found that biliverdin and bilirubin reduced infectivity by blocking viral entry into cells. Results were found to be similar for HIV-2 and SIV. Further research is needed to confirm these results, and to determine whether unconjugated hyperbilirubinemia has any effect on the progression of HIV infection.
Current research has suggested that the anti-oxidant properties of biliverdin and other bile pigments may also have a beneficial effect on asthma
. This is because oxidative stress may play a vital role in the pathogenesis
of asthma. A 2003 study found that asthma patients suffering from jaundice brought on by acute hepatitis B exhibited temporary relief of asthma symptoms. However, there could also have been confounding factors such as elevated levels of cortisol
and epinephrine
, so more research into this possibility is required.
egg shells. There is a significantly higher concentration of biliverdin in blue egg shells than in brown egg shells. Research has shown that the biliverdin of egg shells is produced from the shell gland, rather than from the breakdown of erythrocytes in the blood stream. The presence of biliverdin in egg shells may be an indicator of female fitness, and therefore likely demonstrates evolutionary significance.
Along with its presence in avian egg shells, other studies have also shown that biliverdin is present in the blue-green blood of many marine fish, the blood of tobacco hornworm
, the wings of moth and butterfly, the serum and eggs of frogs, and the placenta of dogs. In the garfish
(Belone belone) and related species, the bones are bright green because of biliverdin.
Biliverdin is also present in the green blood, muscles, bones, and mucosal lining of skinks of the genus Prasinohaema
, found in New Guinea
. It is uncertain whether this presence of biliverdin is an ecological or physiological adaptation of any kind. It has been suggested that accumulation of biliverdin might deter harmful infection by Plasmodium
malaria
parasites, though no statistically significant correlation has been established. The Cambodian frog, Chiromantis samkosensis
also exhibits this character along with turquoise bones.
, biliverdin has been employed as IR-emitting chromophore for in vivo imaging. In contrast to fluorescent proteins which form their chromophore through posttranslational modification
s of the polypeptide chain, phytochromes bind an external ligand
(in this case, biliverdin), and successful imaging of the first bacteriophytochrome-based probe required addition of the exogenous biliverdin. Recent studies demonstrated that bacteriophytochrome-based fluorescent proteins with high affinity to the biliverdin can be imaged in vivo utilizing endogenous ligand only and, thus, with the same easiness as the conventional fluorescent proteins. Advent of the second and further generations of the biliverdin-binding bacteriophytochrome-based probes should broaden possibilities of the non-invasive in vivo imaging.
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
pigment
Pigment
A pigment is a material that changes the color of reflected or transmitted light as the result of wavelength-selective absorption. This physical process differs from fluorescence, phosphorescence, and other forms of luminescence, in which a material emits light.Many materials selectively absorb...
, and is a product of heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...
catabolism
Catabolism
Catabolism is the set of metabolic pathways that break down molecules into smaller units and release energy. In catabolism, large molecules such as polysaccharides, lipids, nucleic acids and proteins are broken down into smaller units such as monosaccharides, fatty acids, nucleotides, and amino...
. It is the pigment responsible for a greenish color sometimes seen in bruise
Bruise
A bruise, also called a contusion, is a type of relatively minor hematoma of tissue in which capillaries and sometimes venules are damaged by trauma, allowing blood to seep into the surrounding interstitial tissues. Bruises can involve capillaries at the level of skin, subcutaneous tissue, muscle,...
s.
Metabolism
Biliverdin results from the breakdown of the heme moiety of hemoglobinHemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
in erythrocytes. Macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s break down senescent erythrocytes and break the heme down into biliverdin, which normally rapidly reduces to free bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
. Biliverdin is seen briefly in some bruises as a green color. Its breakdown into bilirubin in bruises, leads to a yellowish color.
Role in disease
Biliverdin has been found in excess in the blood of humans suffering from hepatic diseases. JaundiceJaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
is caused by the accumulation of biliverdin or bilirubin (or both) in the circulatory system and tissues. Jaundiced skin and sclera
Sclera
The sclera , also known as the white or white of the eye, is the opaque , fibrous, protective, outer layer of the eye containing collagen and elastic fiber. In the development of the embryo, the sclera is derived from the neural crest...
(whites of the eyes) are characteristic of liver failure.
Role in treatment of disease
While typically regarded as a mere waste product of heme breakdown, evidence that suggests that biliverdin — and other bile pigments — has a physiological role in humans has been mounting.Bile pigments such as biliverdin naturally possess significant anti-mutagenic and antioxidant properties and therefore fulfill a useful physiological function. Biliverdin and bilirubin have been shown to be potent scavengers of peroxyl radicals. They have also been shown to inhibit the effects of polycyclic aromatic hydrocarbon
Polycyclic aromatic hydrocarbon
Polycyclic aromatic hydrocarbons , also known as poly-aromatic hydrocarbons or polynuclear aromatic hydrocarbons, are potent atmospheric pollutants that consist of fused aromatic rings and do not contain heteroatoms or carry substituents. Naphthalene is the simplest example of a PAH...
s, heterocyclic amines, and oxidants — all of which are mutagens. Studies have even found that people with higher concentrations levels of bilirubin and biliverdin in their bodies have a lower frequency of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
and cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
.
A 1996 study by McPhee et al. suggested that biliverdin — as well as many other tetrapyrrolic pigments — may function as an HIV-1 protease inhibitor
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
. Of the fifteen compounds tested, biliverdin was one of the most active. In vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
experiments showed that biliverdin and bilirubin competitively inhibited HIV-1 proteases at low micromolar concentrations, reducing viral infectivity
Infectivity
In epidemiology, infectivity refers to the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission that is, how frequently it spreads among hosts that are not in a parent-child relationship...
. However, when tested in cell culture with micromolar concentrations, it was found that biliverdin and bilirubin reduced infectivity by blocking viral entry into cells. Results were found to be similar for HIV-2 and SIV. Further research is needed to confirm these results, and to determine whether unconjugated hyperbilirubinemia has any effect on the progression of HIV infection.
Current research has suggested that the anti-oxidant properties of biliverdin and other bile pigments may also have a beneficial effect on asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
. This is because oxidative stress may play a vital role in the pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of asthma. A 2003 study found that asthma patients suffering from jaundice brought on by acute hepatitis B exhibited temporary relief of asthma symptoms. However, there could also have been confounding factors such as elevated levels of cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, so more research into this possibility is required.
In non-human animals
Biliverdin is an important component of avianBird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
egg shells. There is a significantly higher concentration of biliverdin in blue egg shells than in brown egg shells. Research has shown that the biliverdin of egg shells is produced from the shell gland, rather than from the breakdown of erythrocytes in the blood stream. The presence of biliverdin in egg shells may be an indicator of female fitness, and therefore likely demonstrates evolutionary significance.
Along with its presence in avian egg shells, other studies have also shown that biliverdin is present in the blue-green blood of many marine fish, the blood of tobacco hornworm
Tobacco hornworm
Manduca sexta is a moth of the family Sphingidae present through much of the American continent. Commonly known as the tobacco hornworm, it is closely related to and often confused with the very similar tomato hornworm ; the larvae of both feed on the foliage of various plants from the family...
, the wings of moth and butterfly, the serum and eggs of frogs, and the placenta of dogs. In the garfish
Garfish
The garfish , or sea needle, is a pelagic, oceanodromous needlefish found in brackish and marine waters of the Eastern Atlantic, the Mediterranean Sea, the Baltic Sea, etc. The fish lives close to the surface and has a migratory pattern similar to that of the mackerel, arriving a short time before...
(Belone belone) and related species, the bones are bright green because of biliverdin.
Biliverdin is also present in the green blood, muscles, bones, and mucosal lining of skinks of the genus Prasinohaema
Prasinohaema
Prasinohaema is a genus of skinks characterized by having green blood . This condition is caused by an excess buildup of the bile pigment biliverdin...
, found in New Guinea
New Guinea
New Guinea is the world's second largest island, after Greenland, covering a land area of 786,000 km2. Located in the southwest Pacific Ocean, it lies geographically to the east of the Malay Archipelago, with which it is sometimes included as part of a greater Indo-Australian Archipelago...
. It is uncertain whether this presence of biliverdin is an ecological or physiological adaptation of any kind. It has been suggested that accumulation of biliverdin might deter harmful infection by Plasmodium
Plasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
parasites, though no statistically significant correlation has been established. The Cambodian frog, Chiromantis samkosensis
Chiromantis samkosensis
Chiromantis samkosensis is a moss frog, found in Cambodia in the Cardamom Mountains. It was first described in 2007.-Physical description:...
also exhibits this character along with turquoise bones.
In fluorescence imaging
In a complex with reengineered bacterial phytochromePhytochrome
Phytochrome is a photoreceptor, a pigment that plants use to detect light. It is sensitive to light in the red and far-red region of the visible spectrum. Many flowering plants use it to regulate the time of flowering based on the length of day and night and to set circadian rhythms...
, biliverdin has been employed as IR-emitting chromophore for in vivo imaging. In contrast to fluorescent proteins which form their chromophore through posttranslational modification
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
s of the polypeptide chain, phytochromes bind an external ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
(in this case, biliverdin), and successful imaging of the first bacteriophytochrome-based probe required addition of the exogenous biliverdin. Recent studies demonstrated that bacteriophytochrome-based fluorescent proteins with high affinity to the biliverdin can be imaged in vivo utilizing endogenous ligand only and, thus, with the same easiness as the conventional fluorescent proteins. Advent of the second and further generations of the biliverdin-binding bacteriophytochrome-based probes should broaden possibilities of the non-invasive in vivo imaging.