Angelicin

Humans have used plants rich in angelicin for centuries. The earliest known record dates back to 3000 BC when ancient Egyptians applied the oil and sap of local Apiaceae species exposing their skin to sunlight to cure vitiligo. In meantime, tribes in India used Psoralea corylifolia which contained psoralen, the isomer of angelicin. Humans also attempted to harvest the plants as an alternative food source. However, most of them turned out to be unpalatable and toxic such as Angelica archangelica due to the ability to irritate skin and damage internal organs. The name "angelicin" stems from the aforementioned plant, Angelica. This Latin name originated in medieval Europe where this plant was also used as a universal treatment to many types of disease not mentioning the bubonic plague. At this time, people believed that the plant could prevent the soul from being taken over by sorcery, curse and evil spirit (add reference). Angelica would have appeared in a dream with an angel explaining its applications, hence the name. Ironically, it was later discovered that the plant's oil is toxic when utilized in large quantities particularly when the plant was fresh. The species of plants where angelicin is found was introduced in Britain in the 19th century. Currently, it can be found in Canada and some parts of the United States and Europe. Because of the toxicity of certain plant parts and the ability of plant to proliferate, it is included in the list of invasive species. The leaves of Angelica archangelica, which are rich in angelicin, are used to extract the compound. There were multiple studies on the toxicity of angelicin one of which showed that the compound elicits chromosomal damage in hamster cells exposed to 320-380 nm UV light. The chromosomal aberrations were shown to be also induced in humans. Nowadays, it is debated whether Angelica should be considered toxic. However, it is certain that the toxicity is dependent on the dose of angelicin administered and is solely the matter of experts when it comes to its application. == Biological synthesis ==

and angelicin synthase shows a 70% identity overall and 40% identity in the substrate recognition sites. This implies that the biosynthesis of angelicin is a relatively recently evolved trait. == Chemical synthesis ==

File:Iodination of Umbelliferone.png|alt=Iodination of Umbelliferone.|left|thumb|Iodination of umbelliferone. The compound can be isolated from natural sources, albeit this affords a low yield due to the prevalence of other furanocoumarins. The popular technique is air drying the aerial parts and ground roots of plant followed by n-hexane extraction and column chromatography over silica gel. == Medical use ==

Angelicin derivatives are used to treat psoriasis and cancer. One way of treating these diseases is by photochemotherapy (PUVA) which combines UV irradiation with photosensitizing chemical. In most cases the 4,5’-dimethylangelicin is applied owing to its firm binding and specificity to DNA. Also, it was shown that it is actively inhibits the synthesis of nucleic acids in tumor cells thereby decreasing their growth. In PUVA, angelicin is less popular than psoralen, although both furanocoumarins are photosensitizing and used in couple with long-wave UV irradiation. Angelicin and psoralen are used in other skin disorders such as vitiligo and mycosis. DNA photobinding is the most studied aspect of the photobiology and photochemistry of angelicin. According to the mechanism, long-range UV light triggers angelicin to bind to the pyrimidine bases of DNA in the same manner as psoralen. In this way, the inhibition of DNA replication via the formation of photoadducts can occur. This might be the basis for the desired therapeutic effect as in the case of psoralen derivatives. == Interaction with biomolecules ==

in a manner similar to the formation of pyrimidine adducts. File:The product of angelicin cycloaddition with linoleic ester..jpg|alt=The product of angelicin cycloaddition with linoleic ester.|left|thumb|294x294px|The product of angelicin cycloaddition with the ester of linoleic acid. == Toxicity ==

According to the MSDS of Sigma-Aldrich, the LD50 of angelicin is 322 mg/kg which shows acute toxicity if orally administered to rats. The possible consequences are alteration in circadian rhythm and righting reflex, ataxia and analgesia. Through its presence in plants such as Angelica archangelica, angelicin was shown to have toxic effects on humans, notably by causing skin irritability and organ damage. leading to severe skin damage such as erythema and blisters. Upon irradiation with UV light of longer wavelength, angelicin forms DNA monoadducts which can cause skin cancer. Both psoralen and angelicin can be used in cancer therapeutics to suppress DNA replication in tumor cells and induce apoptosis – as mentioned in medical use – but they should be handled with care as they can cause photodermatitis in healthy cells as a side effect. The inhibition is due to the fact that angelicin decreases the activity and expression of CYP1A1 which is regulated by aryl hydrocarbon receptors (AhR). There are three hypotheses proposed to explain the phenomenon: • Angelicin attenuates the catalytic activity performed by CYP1A1 regardless the presence of UV light. • Angelicin triggers the gene expression of CYP1A1 by activation of AhR when no UV light is available. • Angelicin leads to CYP1A1 gene expression without the involvement of AhR. The phototoxic properties of angelicin were deployed by its use as a natural pesticide and disinfectant. Note that it is difficult to readily determine whether only angelicin poses the highest risk of phototoxicity and photomutagenicity as in plants angelicin always occurs in a mixture with angelicin derivatives, psoralen and other furanocoumarins. Moreover, the furanocoumarin composition of most plant species is not definitely known as well as the toxic properties of some furanocoumarins. ==References==