Biliverdin

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 bruises.

Metabolism
Biliverdin results from the breakdown of the heme moiety of hemoglobin in erythrocytes. Macrophages 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.

Role in disease
Biliverdin has been found in excess in the blood of humans suffering from hepatic diseases. Jaundice 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.

Role in treatment of disease
While typically regarded as a mere waste product of heme breakdown, evidence has been mounting that suggests biliverdin—and other bile pigments—has a physiological role in humans.

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 hydrocarbons, 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 examine if 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.

In non-human animals
Biliverdin is an important component of avian 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 is likely evolutionarily important.

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.

In fluorescence imaging
In a complex with reengineered bacterial phytochrome, biliverdin has been employed as IR-emitting chromophore for in vivo imaging. In contrast to fluorescent proteins which form their chromophore through posttranslational modifications of the polypeptide chain, phytochromes bind an external ligand (in this case, biliverdin), and successful imaging of the first bachteriophytochrome-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.