Angelicin

Last updated
Angelicin
Angelicin 200.svg
Names
Pronunciationˈeɪn.dʒəlaɪ.sɪn
Preferred IUPAC name
2H-Furo[2,3-h][1]benzopyran-2-one
Other names
Isopsoralen, 2H-furo[2,3-h]chromen-2-one, furo[2,3-h]chromen-2-one
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.164.795 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C11H6O3/c12-10-4-2-7-1-3-9-8(5-6-13-9)11(7)14-10/h1-6H Yes check.svgY
    Key: XDROKJSWHURZGO-UHFFFAOYSA-N Yes check.svgY
  • InChI=1S/C11H6O3/c12-10-4-2-7-1-3-9-8(5-6-13-9)11(7)14-10/h1-6H
  • O=C\2Oc3c1ccoc1ccc3/C=C/2
Properties
C11H6O3
Molar mass 186.166 g·mol−1
Appearancepale yellow crystals [1]
Melting point 134°C
Boiling point 362.6°C
10 mM in DMSO
log P 1.97 [2]
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
photosensitizer, vesicant, carcinogen
Flash point 173.1°C
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Angelicin is the parent compound in a family of naturally occurring organic compounds known as the angular furanocoumarins. Structurally, it can be considered as benzapyra-2-one fused with a furan moiety in the 7,8-position. Angelicin is commonly found in certain Apiaceae and Fabaceae plant species such as Bituminaria bituminosa . It has a skin permeability coefficient (LogKp) of -2.46. [2] The maximum absorption is observed at 300 nm. [3] The 1HNMR spectrum is available; [1] the infrared and mass spectra of angelicin can be found in this database. The sublimation of angelicin occurs at 120 °C and the pressure of 0.13 Pa. [4] Angelicin is a coumarin.

Contents

History and etymology

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. [5]

Angelica archangelica Angelica archangelica01.jpg
Angelica archangelica

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. [6]

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. [7]

The leaves of Angelica archangelica, which are rich in angelicin, are used to extract the compound. [8] 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. [9] 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

The general biosynthesis of angular furanocoumarins. Angelicin is illustrated as a final product. The general biosynthesis pathway of angular furanocoumarins.jpg
The general biosynthesis of angular furanocoumarins. Angelicin is illustrated as a final product.

The biosynthesis of angelicin can be described as a variation in the biological synthesis of furanocoumarins. It begins from the capture of organic carbon by photosynthesis and the formation of carbohydrates. Subsequently, the carbohydrates become the substrates of the shikimic acid pathway where they are converted to phenylalanine and tyrosine. Enzymes such as ammonialyases, methylases and hydroxylases then transform these amino acids to cinnamic acid derivatives which undergo o-hydroxylation yielding coumarins. The coumarins can undergo further reactions such as prenylation and oxidation to give multiple furanocoumarins one of which is angelicin. [10]

The synthesis of p-coumaric acid from phenylalanine. The first steps of angelicin biosynthesis.jpg
The synthesis of p-coumaric acid from phenylalanine.

Here, the biosynthesis of angelicin is described in more detail starting at L-phenylalanine as a precursor. The phenylalanine undergoes a non-oxidative deamination by phenylalanine ammonia-lyase (PAL) to trans-cinnamic acid. Afterwards, the trans-cinnamic acid is hydroxylated at the para position by trans-cinnamate 4-monooxygenase (C4H) which utilizes NADPH, H+ and O2. The product, p-coumaric acid, is then converted to umbelliferone, the important intermediate of biosynthesis pathway. [11]

O-hydroxylation and photoisomerization of p-coumaric acid to umbelliferone. Umbelliferone formation.jpg
O-hydroxylation and photoisomerization of p-coumaric acid to umbelliferone.

4-Coumaric acid 2-hydroxylase (C2’H) hydroxylates the p-coumaric acid at the ortho position. Notably, this reaction uses alpha-ketoglutarate which is reduced to succinate both of which are involved in the Krebs cycle. The newly formed trans-dihydrocinnamic acid undergoes a photochemical isomerization to a cis isomer which spontaneously lactonizes to yield umbeliferone. [12]

Formation of angelicin from umbelliferone. Formation of angelicin from umbelliferone.jpg
Formation of angelicin from umbelliferone.

Subsequently, umbelliferone 6-prenyltransferase (PT) couples umbelliferone with prenyl diphosphate to give osthenol and pyrophosphate. Osthenol is oxidized to (+)-columbianetin by (+)-columbianetin synthase (CS), a putative plant cytochrome P450, although the details of this reaction are not clear. The biosynthesis is terminated with the oxidation of (+)-columbianetin yielding angelicin by angelicin synthase (AS) which is also considered as the enzyme of cytochrome P450 family. [13]

It is noteworthy that the biosynthesis of angelicin diverges at the umbelliferone as it is also converted to psoralen, the isomer of angelicin. In fact, psoralen, from which the family of linear furanocoumarins descends, is by far much more abundant in plants than angelicin. As a result, most herbivorous insects are resistant to psoralen. Now, it is increasingly recognized that plants devised the pathway leading to angelicin as an alternative defense mechanism. For example, angelicin enhances the toxicity of psoralen by acting as an inhibitor of the detoxifying cytochrome P450 in insects. [14] Moreover, the comparison of the protein sequences of psoralen synthase and angelicin synthase shows a 70% identity overall and 40% identity in the substrate recognition sites. [13] This implies that the biosynthesis of angelicin is a relatively recently evolved trait.

Chemical synthesis

Iodination of umbelliferone. Iodination of Umbelliferone.png
Iodination of umbelliferone.
Vaginol synthesis from umbelliferone derivative. Vaginol synthesis.png
Vaginol synthesis from umbelliferone derivative.
Formation of angelicin from vaginol. Vaginol to Angelicin.png
Formation of angelicin from vaginol.

Iodination of commercially available umbelliferone (7-hydroxycoumarin) yields 7-hydroxy-8-iodocoumarin. Acetoxy group can be introduced into hydroxyl of 7-hydroxy-8-iodocoumarin, which is used to create vaginol or vaginidiol with an isopropyl Grignard reagent and commercially available epoxy aldehydes. Subsequent acid-catalysed fragmentation of vaginol with dichloromethane in trifluoroacetic acid yields angelicin. [15]

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. [1] [16]

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. [17] [18] 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. [19]

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. [20] 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. [17]

However, extreme care should be taken while using PUVA due to the side effects it may bring. Therefore, this type of treatment is sometimes used as a last resort and often corticosteroids are used instead. [18] One of the main adverse effects of PUVA is phototoxicity which can be tackled by heteroanalogues of angelicin. For example, recently researchers have shown that if furan ring is replaced by 1-substituted pyrazole or thiophene ring, the new angelicin heteroanalogues show virtually no phototoxicity. [21]

Interaction with biomolecules

Thymidine adduct of angelicin. Deoxythymidine adduct of angelicin.jpg
Thymidine adduct of angelicin.

It was shown that angelicin exhibits a multifaceted effect on various biomolecules which stem from the compound’s structure and photoreactivity. For example, the planar structure allows angelicin to intercalate between the DNA bases. When exposed to ultraviolet light, it undergoes a C4-photocycloaddition reaction with thymine and cytosine forming a monoadduct. The double bonds of angelicin involved in this reaction are the 3,4 and 4’,5’. [22] However, the rest of the angelicin’s aromatic system cannot react with the pyrimidine of complementary strand owing to the unfavorable alignment of reactive double bonds. [23] Lipids are also susceptible to the photoinduced reactions with angelicin which can be either aerobic or anaerobic. The aerobic reactions cause lipid peroxidation [24] whereas the anaerobic pathway leads to the conjugation of angelicin with unsaturated fatty acid chains such as linolenic acid in a manner similar to the formation of pyrimidine adducts. [25]

The product of angelicin cycloaddition with the ester of linoleic acid. The product of angelicin cycloaddition with linoleic ester..jpg
The product of angelicin cycloaddition with the ester of linoleic acid.

Proteins were demonstrated to interact with angelicin in a non-covalent fashion. For instance, there is a measurable affinity of angelicin towards human serum albumin (19.10 × 104 mol−1L−1) which has one non-covalent binding site per angelicin molecule. The ultraviolet light (365 nm) facilitates its covalent binding to proteins which is enhanced in the presence of oxygen. At this wavelength, angelicin can also modify certain amino acids. [26] [27] [28]

Toxicity

According to the MSDS of Sigma-Aldrich, [29] 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.

Angelicin demonstrates phototoxic and photomutagenic effects when in contact with skin. It enhances the sensitivity of skin to UV light [30] leading to severe skin damage such as erythema and blisters. [31] [32] Upon irradiation with UV light of longer wavelength, angelicin forms DNA monoadducts which can cause skin cancer. [32] In contrast, the isomer of angelicin, psoralen, was reported to be five to ten times more active than angelicin and cross-link DNA . This impedes DNA replication more prominently due to the inability for the two strands of DNA helix to separate. [33] 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. [30] [33]

In mammalian cell cultures, angelicin showed mutagenic and cytotoxic effects while playing a role of strong inhibitor of drug metabolism. [34] 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: [34]

  1. Angelicin attenuates the catalytic activity performed by CYP1A1 regardless the presence of UV light.
  2. Angelicin triggers the gene expression of CYP1A1 by activation of AhR when no UV light is available.
  3. 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. [32]

Related Research Articles

PUVA is an ultraviolet light therapy treatment for skin diseases: vitiligo, eczema, psoriasis, graft-versus-host disease, mycosis fungoides, large plaque parapsoriasis, and cutaneous T-cell lymphoma, using the sensitizing effects of the drug psoralen. The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA.

<span class="mw-page-title-main">Action spectrum</span> Graph of the rate of biological effectiveness plotted against wavelength of light

An action spectrum is a graph of the rate of biological effectiveness plotted against wavelength of light. It is related to absorption spectrum in many systems. Mathematically, it describes the inverse quantity of light required to evoke a constant response. It is very rare for an action spectrum to describe the level of biological activity, since biological responses are often nonlinear with intensity.

<span class="mw-page-title-main">Methoxsalen</span> Chemical compound

Methoxsalen sold under the brand name Oxsoralen among others, is a medication used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to ultraviolet (UVA) light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. Levels of individual patient PUVA exposure were originally determined using the Fitzpatrick scale. The scale was developed after patients demonstrated symptoms of phototoxicity after oral ingestion of methoxsalen followed by PUVA therapy. Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarins. They consist of coumarin annulated with furan. It can also be injected and used topically.

<span class="mw-page-title-main">Avobenzone</span> UV-A protectant used in sunscreens

Avobenzone is an organic molecule and an oil-soluble ingredient used in sunscreen products to absorb the full spectrum of UVA rays.

<span class="mw-page-title-main">Octyl methoxycinnamate</span> UV-B protectant used in sunscreens

Octyl methoxycinnamate or ethylhexyl methoxycinnamate (INCI) or octinoxate (USAN), trade names Eusolex 2292 and Uvinul MC80, is an organic compound that is an ingredient in some sunscreens and lip balms. It is an ester formed from methoxycinnamic acid and 2-ethylhexanol. It is a liquid that is insoluble in water.

<span class="mw-page-title-main">Umbelliferone</span> Chemical compound

Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a natural product of the coumarin family.

<span class="mw-page-title-main">Psoralen</span> Chemical compound

Psoralen is the parent compound in a family of naturally occurring organic compounds known as the linear furanocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone. Psoralen occurs naturally in the seeds of Psoralea corylifolia, as well as in the common fig, celery, parsley, West Indian satinwood, and in all citrus fruits. It is widely used in PUVA treatment for psoriasis, eczema, vitiligo, and cutaneous T-cell lymphoma; these applications are typically through the use of medications such as Methoxsalen. Many furanocoumarins are extremely toxic to fish, and some are deposited in streams in Indonesia to catch fish.

<span class="mw-page-title-main">Padimate O</span> Water-insoluble oily ingredient used in some sunscreens

Padimate O is an organic compound related to the water-soluble compound PABA that is used as an ingredient in some sunscreens. This yellowish water-insoluble oily liquid is an ester formed by the condensation of 2-ethylhexanol with dimethylaminobenzoic acid. Other names for padimate O include 2-ethylhexyl 4-dimethylaminobenzoate, Escalol 507, octyldimethyl PABA, and OD-PABA.

Photoprotection is the biochemical process that helps organisms cope with molecular damage caused by sunlight. Plants and other oxygenic phototrophs have developed a suite of photoprotective mechanisms to prevent photoinhibition and oxidative stress caused by excess or fluctuating light conditions. Humans and other animals have also developed photoprotective mechanisms to avoid UV photodamage to the skin, prevent DNA damage, and minimize the downstream effects of oxidative stress.

<span class="mw-page-title-main">Furanocoumarin</span> Class of organic chemical compounds

The furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. Most of the plant species found to contain furanocoumarins belong to a handful of plant families. The families Apiaceae and Rutaceae include the largest numbers of plant species that contain furanocoumarins. The families Moraceae and Fabaceae include a few widely distributed plant species that contain furanocoumarins.

<span class="mw-page-title-main">Bergamottin</span> Chemical compound

Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived.

<span class="mw-page-title-main">Phycocyanobilin</span> Chemical compound

Phycocyanobilin is a blue phycobilin, i.e., a tetrapyrrole chromophore found in cyanobacteria and in the chloroplasts of red algae, glaucophytes, and some cryptomonads. Phycocyanobilin is present only in the phycobiliproteins allophycocyanin and phycocyanin, of which it is the terminal acceptor of energy. It is covalently linked to these phycobiliproteins by a thioether bond.

<span class="mw-page-title-main">Trioxsalen</span> Chemical compound

Trioxsalen (trimethylpsoralen (TMP), trioxysalen (INN) or Trisoralen) is a furanocoumarin and a psoralen derivative. It is obtained from several plants, mainly Psoralea corylifolia. Like other psoralens it causes photosensitization of the skin. It is administered either topically or orally in conjunction with UV-A (the least damaging form of ultraviolet light) for phototherapy treatment of vitiligo and hand eczema. After photoactivation it creates interstrand cross-links in DNA, which can cause programmed cell death unless repaired by cellular mechanisms. In research it can be conjugated to dyes for confocal microscopy and used to visualize sites of DNA damage. The compound is also being explored for development of antisense oligonucleotides that can be cross-linked specifically to a mutant mRNA sequence without affecting normal transcripts differing at even a single base pair.

A photocarcinogen is a substance which causes cancer when an organism is exposed to it, then illuminated. Many chemicals that are not carcinogenic can be photocarcinogenic when combined with exposure to light, especially UV. This can easily be understood from a photochemical perspective: The reactivity of a chemical substance itself might be low, but after illumination it transitions to an excited state, which is chemically much more reactive and therefore potentially harmful to biological tissue and DNA. Light can also split photocarcinogens, releasing free radicals, whose unpaired electrons cause them to be extremely reactive.

Tanning activators are chemicals that increase the effect of UV-radiation on the human skin.

<span class="mw-page-title-main">Phytophotodermatitis</span> Medical condition

Phytophotodermatitis, also known as berloque dermatitis, margarita photodermatitis, lime disease or lime phytodermatitis is a cutaneous phototoxic inflammatory reaction resulting from contact with a light-sensitizing botanical agent followed by exposure to ultraviolet A (UV-A) light. Symptoms include erythema, edema, blisters, and delayed hyperpigmentation. Heat and moisture tend to exacerbate the reaction.

<span class="mw-page-title-main">Bergapten</span> Chemical compound

Bergapten (5-methoxypsoralen) is a naturally-occurring organic chemical compound produced by numerous plant species, especially from the carrot family Apiaceae and the citrus family Rutaceae. For example, bergapten has been extracted from 24 species of the genus Heracleum in the family Apiaceae. In the family Rutaceae, various Citrus species contain significant amounts of bergapten, especially the bergamot orange, the micrantha, and certain varieties of lime and bitter orange.

<span class="mw-page-title-main">Isopimpinellin</span> Chemical compound

Isopimpinellin is a natural product synthesized by numerous plant species, especially species in the carrot family Apiaceae. The compound can be found in celery, garden angelica, parsnip, fruits and in the rind and pulp of limes. Several studies have looked into the effects of isopimpinellin and other furanocoumarins as anticarcinogens. These studies have shown possible inhibition of 7,12-Dimethylbenz(a)anthracene, which are initiators of skin tumors. Evidence has also been reported that links these compounds to the inhibition of breast cancers.

<span class="mw-page-title-main">Bergamot essential oil</span> Cold-pressed essential oil

Bergamot essential oil is a cold-pressed essential oil produced by cells inside the rind of a bergamot orange fruit. It is a common flavoring and top note in perfumes. The scent of bergamot essential oil is similar to a sweet light orange peel oil with a floral note.

<span class="mw-page-title-main">Marmesin</span> Chemical compound

Marmesin (nodakenetin) is a chemical compound precursor in psoralen and linear furanocoumarins biosynthesis.

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  4. ↑ Böhme, Horst; Severin, Theodor (1957). "Optische Untersuchungen an Cumarinen Mitteilung: Die Ultraviolettabsorption einiger Cumarine pflanzlicher Herkunft". Archiv der Pharmazie. 290 (10): 486–494. doi:10.1002/ardp.19572901010. ISSN   1521-4184. PMID   13471015. S2CID   84020911.
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  14. ↑ Stanjek, Volker; Boland, Wilhelm (1998-09-09). "Biosynthesis of Angular Furanocoumarins: Mechanism and Stereochemistry of the Oxidative Dealkylation of Columbianetin to Angelicin in Heracleum mantegazzianum (Apiaceae)". Helvetica Chimica Acta. 81 (9): 1596–1607. doi:10.1002/(SICI)1522-2675(19980909)81:9<1596::AID-HLCA1596>3.0.CO;2-F.
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  21. ↑ Mosti, L.; Lo Presti, E.; Menozzi, G.; Marzano, C.; Baccichetti, F.; Falcone, G.; Filippelli, W.; Piucci, B. (August 1998). "Synthesis of angelicin heteroanalogues: preliminary photobiological and pharmacological studies". Farmaco (Societa Chimica Italiana: 1989). 53 (8–9): 602–610. doi:10.1016/S0014-827X(98)00076-7. hdl: 11577/2470046 . ISSN   0014-827X. PMID   10081825.
  22. 1 2 Caffieri, S.; Lucchini, V.; Rodighiero, P.; Miolo, G.; Dall'Acqua, F. (November 1988). "3,4 and 4',5'-photocycloadducts between 4'-methylangelicin and thymine from DNA". Photochemistry and Photobiology. 48 (5): 573–577. doi:10.1111/j.1751-1097.1988.tb02866.x. ISSN   0031-8655. PMID   3241830. S2CID   32844266.
  23. ↑ Dall'Acqua, F.; Marciani, S.; Ciavatta, L.; Rodighiero, G. (1971). "Formation of inter-strand cross-linkings in the photoreactions between furanocoumarins and DNA". Zeitschrift für Naturforschung B. 26 (6): 561–569. doi: 10.1515/znb-1971-0613 . PMID   4397973.
  24. ↑ Dall'Acqua, F.; Martelli, P. (February 1991). "Photosensitizing action of furocoumarins on membrane components and consequent intracellular events". Journal of Photochemistry and Photobiology B: Biology. 8 (3): 235–254. doi:10.1016/1011-1344(91)80082-S. ISSN   1011-1344. PMID   1904925.
  25. 1 2 Caffieri, S.; Daga, A.; Vedaldi, D.; Dall'Acqua, F. (1988-12-01). "Photoaddition of angelicin to linolenic acid methyl ester". Journal of Photochemistry and Photobiology B: Biology. 2 (4): 515–521. doi:10.1016/1011-1344(88)85080-2. ISSN   1011-1344. PMID   3150003.
  26. ↑ Veronese, FM; Bevilacqua, R; Schiavon, O; Rodighiero, G (1979). "Drug-protein interaction: plasma protein binding of furocoumarins". Il Farmaco; Edizione Scientifica. 34 (8): 716–25. ISSN   0430-0920. PMID   467637.
  27. ↑ Veronese, F. M.; Schiavon, O.; Bevilacqua, R.; Bordin, F.; Rodighiero, G. (1982-07-01). "Photoinactivation of Enzymes by Linear and Angular Furocoumarins". Photochemistry and Photobiology. 36 (1): 25–30. doi:10.1111/j.1751-1097.1982.tb04335.x. ISSN   1751-1097. PMID   6287507. S2CID   42986954.
  28. ↑ Veronese, F. M.; Schiavon, O.; Bevilacqua, R.; Bordin, F.; Rodighiero, G. (1981-09-01). "The Effect of Psoralens and Angelicins on Proteins in the Presence of Uv-a Irradiation". Photochemistry and Photobiology. 34 (3): 351–354. doi:10.1111/j.1751-1097.1981.tb09369.x. ISSN   1751-1097. PMID   7280051.
  29. ↑ "Material Safety Data Sheet" (PDF). Sigma-Aldrich.
  30. 1 2 E. Gorgus, C. Lohr, N. Raquet, S. Guth, and D. Schrenk. Limettin and furocoumarins in beverages containing citrus juices or extracts . Food and Chemical Toxicology, 48(1):93–98, 2010.
  31. ↑ B. V. Davidov A. Ya. Potapenko, V. L. Sukhorukov. A comparison between skin-photosensitizing activities of 8-methoxypsoralen and angelicin. Experientia 40, pages 264–265, 1982.
  32. 1 2 3 Christiane Lohr, Nicole Raquet, and Dieter Schrenk. Application of the concept of relative photomutagenic potencies to selected furocoumarins in V79 cells. Toxicology in Vitro, 24(2):558–566, 2010.
  33. 1 2 Alley, Amanda (August 1987). "Parsnips and furocoumarins". Food and Chemical Toxicology. 25 (8): 634–635. doi:10.1016/0278-6915(87)90033-0.
  34. 1 2 Baumgart, Annette; Schmidt, Melanie; Schmitz, Hans-Joachim; Schrenk, Dieter (15 February 2005). "Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes". Biochemical Pharmacology. 69 (4): 657–667. doi:10.1016/j.bcp.2004.11.017. PMID   15670584.
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