Methoxsalen, sold under the brand name Oxsoralen among others, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
used to treat
psoriasis
Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...
,
eczema
Dermatitis is inflammation of the Human skin, skin, typically characterized by itchiness, erythema, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become lichenification, thick ...
,
vitiligo
Vitiligo is a disorder that causes the skin to lose its color. Specific causes are unknown but studies suggest a link to immune system changes.
Signs and symptoms
The only sign of vitiligo is the presence of pale patchy areas of depigmen ...
, and some
cutaneous lymphomas in conjunction with exposing the skin to
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
(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 Fitzpatrick scale (also Fitzpatrick skin typing test; or Fitzpatrick phototyping scale) is a numerical classification schema for human skin color. It was developed in 1975 by American dermatologist Thomas B. Fitzpatrick as a way to estimate th ...
. The scale was developed after patients demonstrated symptoms of
phototoxicity
Phototoxicity, also called photoirritation, is a chemically induced skin irritation, requiring light, that does not involve the immune system. It is a type of photosensitivity.
The skin response resembles an exaggerated sunburn. The involved chemi ...
after oral ingestion of methoxsalen followed by PUVA therapy.
Chemically, methoxsalen belongs to a class of organic natural molecules known as
furanocoumarin
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 Rutacea ...
s. They consist of
coumarin
Coumarin () or 2''H''-chromen-2-one is an aromatic organic chemical compound with formula . Its molecule can be described as a benzene molecule with two adjacent hydrogen atoms replaced by a lactone-like chain , forming a second six-membered h ...
annulated with
furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as furans.
Furan is a colorless, flammable, highly ...
. It can also be injected and used topically.
Natural sources
In 1947, methoxsalen was isolated (under the name "ammoidin") from the plant ''
Ammi majus
''Ammi majus'', commonly called bishop's flower, false bishop's weed, laceflower, bullwort, etc., is a member of the carrot family Apiaceae. The plant, which has white lace-like flower clusters, has a large distribution through Southern Europe, ...
'', bishop's weed.
In 1970, Nielsen extracted 8-methoxypsoralen from four species of the genus ''
Heracleum'' in the carrot family
Apiaceae
Apiaceae or Umbelliferae is a family of mostly aromatic flowering plants named after the type genus ''Apium'' and commonly known as the celery, carrot or parsley family, or simply as umbellifers. It is the 16th-largest family of flowering plants ...
, including ''
Heracleum mantegazzianum
''Heracleum mantegazzianum'', commonly known as giant hogweed, is a monocarpic perennial herbaceous plant in the carrot family Apiaceae. ''H. mantegazzianum'' is also known as cartwheel-flower, giant cow parsley, giant cow parsnip, or hogs ...
'' and ''
Heracleum sphondylium
''Heracleum sphondylium'', commonly known as hogweed, common hogweed or cow parsnip, is a herbaceous perennial or biennial plant, in the umbelliferous family Apiaceae that includes fennel, cow parsley, ground elder and giant hogweed. It is nat ...
''. An additional 32 species of the genus ''Heracleum'' were found to contain 5-methoxypsoralen (
bergapten
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 ...
) or other
furanocoumarin
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 Rutacea ...
s.
Biosynthesis
The biosynthetic pathway is a combination of the
shikimate
Shikimic acid, more commonly known as its anionic form shikimate, is a cyclohexene, a cyclitol and a cyclohexanecarboxylic acid. It is an important biochemical metabolite in plants and microorganisms. Its name comes from the Japanese flower ''sh ...
pathway, which produces
umbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and ''beta''-umbelliferone, is a natural product of the coumarin family.
It absorbs ultraviolet light strongly at several wavelengths. There are some indications that this ch ...
, and the
mevalonate pathway
The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl ...
.
Synthesis of umbelliferone
Umbelliferone is a
phenylpropanoid
The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acids phenylalanine and tyrosine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of ...
and as such is synthesized from
L-phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...
, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into
cinnamic acid
Cinnamic acid is an organic compound with the formula C6H5-CH=CH- COOH. It is a white crystalline compound that is slightly soluble in water, and freely soluble in many organic solvents. Classified as an unsaturated carboxylic acid, it occurs n ...
, followed by
hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
by
cinnamate 4-hydroxylase
In enzymology, a trans-cinnamate 4-monooxygenase () is an enzyme that catalyzes the chemical reaction
:trans-cinnamate + NADPH + H+ + O2 \rightleftharpoons 4-hydroxycinnamate + NADP+ + H2O
The 4 substrates of this enzyme are trans-cinnamate, ...
to yield
4-coumaric acid. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid (
umbellic acid
Umbellic acid (2,4-dihydroxycinnamic acid) is a hydroxycinnamic acid. It is an isomer of caffeic acid.
It is a precursor in the umbelliferone biosynthesis pathway. Umbelliferone is a phenylpropanoid and as such is synthesized from L-phenylalani ...
) followed by a bond rotation of the unsaturated bond adjacent to the
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the
lactone
Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring.
Lactones are formed by intramolecular esterification of the co ...
umbelliferone.
Synthesis of methoxsalen
The biosynthetic route then continues with the activation of
dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosynt ...
(DMAPP), produced via the mevalonate pathway, to form a carbo-cation via the cleavage of the diphosphates. Once activated, the enzyme umbelliferone 6-prenyltransferase catalyzes a C-alkylation between DMAPP and umbelliferone at the activated position ortho to the phenol, yielding demethylsuberosin. This is then followed by a hydroxylation catalyzed by the enzyme marmesin synthase to yield
marmesin
Marmesin (nodakenetin) is a chemical compound precursor in psoralen and linear furanocoumarins biosynthesis
Biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. I ...
. Another hydroxylation is catalyzed by
psoralen synthase to yield
psoralen
Psoralen (also called psoralene) 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 a ...
. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme
xanthotoxol O-methyltransferase and
S-adenosyl methionine
''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
to yield methoxsalen.
Risks and side effects
Patients with
high blood pressure
Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
or a history of
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
problems are at risk for inflammation and irreparable damage to both liver and skin. The eyes must be protected from UVA radiation. Side effects include
nausea
Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
headache
Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches.
Headaches can occur as a result ...
s,
dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
, and in rare cases
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
.
Methoxsalen has also been classified as an
IARC Group 1 carcinogen
Substances, mixtures, and exposure circumstances in this list have been classified as group 1 by the International Agency for Research on Cancer (IARC): The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures tha ...
(known to cause cancer) but is only cancerous when combined with light - UVA radiation.
Society and culture
Author
John Howard Griffin
John Howard Griffin (June 16, 1920 – September 9, 1980) was an American journalist and author from Texas who wrote about and championed racial equality. He is best known for his 1959 project to temporarily pass as a African Americans, black man ...
(1920–1980) used the chemical to darken his skin in order to investigate racial segregation in the American South. He wrote the book ''
Black Like Me
''Black Like Me'', first published in 1961, is a nonfiction book by journalist John Howard Griffin recounting his journey in the Deep South of the United States, at a time when African-Americans lived under racial segregation. Griffin was a nat ...
'' (1961) about his experiences.
References
External links
*
{{Portal bar , Medicine
CYP3A4 inhibitors
Photosensitizing agents
IARC Group 1 carcinogens
Furanocoumarins
O-methylated coumarins
Catechol ethers
General cytochrome P450 inhibitors
Orphan drugs
Plant toxins