Methoxsalen
Encyclopedia
Methoxsalen is a drug
used to treat psoriasis
, eczema
, vitiligo
, and some cutaneous Lymphomas
in conjunction with exposing the skin to sunlight. Methoxsalen is extracted from Ammi majus
, a plant of the family Apiaceae
. Methoxsalen modifies the way skin cells receive the UVA
radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA
(psoralen
+ UVA) light treatment. The substance is also present in other Apiaceae as well as Rutaceae
, for example bergamot
oil which is used in many perfumes and aromatherapy oils.
Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarin
s. They consist of coumarin
annulated with furan
.
, and the mevalonate pathway.
and as such is synthesized from L-phenylalanine, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into cinnamic acid
, followed by hydroxylation
by cinnamate 4-hydroxylase to yield 4-coumaric acid
. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid followed by a bond rotation of the unsaturated bond adjacent to the carboxylic acid
group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the lactone
umbelliferone.
The biosynthetic route then continues with the activation of dimethylallyl pyrophosphate
(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. Another hydroxylation is catalyzed by psoralen synthase
to yield psoralen
. 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
to yield methoxsalen.
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
, headache
s, dizziness
, and in rare cases insomnia
.
used the chemical to darken his skin in order to investigate racial segregation in the south. He wrote the non-fiction book Black Like Me about his experiences.
Some cologne/perfume contains bergamot oil as one of the ingredients (for the scent). People wearing the concoction on places where the skin receives UV radiation
was radiated by the sun noticed that their skin turned brownish at those spots (due to the phototoxic effects of methoxsalen present in the bergamot oil). Most modern formulations of perfumes containing bergamot are de-methoxsalenised.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
used to treat psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
, eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...
, vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
, and some cutaneous Lymphomas
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
in conjunction with exposing the skin to sunlight. Methoxsalen is extracted from Ammi majus
Ammi majus
Ammi majus, commonly known as bishop's flower, bishop’s weed, false bishop’s weed, bullwort, greater ammi, lady’s lace, Queen Anne's lace or laceflower, originates in the Nile River Valley and has white lace-like flower clusters...
, a plant of the family Apiaceae
Apiaceae
The Apiaceae , commonly known as carrot or parsley family, is a group of mostly aromatic plants with hollow stems. The family is large, with more than 3,700 species spread across 434 genera, it is the sixteenth largest family of flowering plants...
. Methoxsalen modifies the way skin cells receive the UVA
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA
PUVA
PUVA is a psoralen + UVA treatment for eczema, psoriasis, graft-versus-host disease and vitiligo, and mycosis fungoides. The psoralen is applied or taken orally to sensitize the skin, then the skin is exposed to UVA. Long term use has been associated with higher rates of skin cancer.Psoralens are...
(psoralen
Psoralen
Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...
+ UVA) light treatment. The substance is also present in other Apiaceae as well as Rutaceae
Rutaceae
Rutaceae, commonly known as the rue or citrus family, is a family of flowering plants, usually placed in the order Sapindales.Species of the family generally have flowers that divide into four or five parts, usually with strong scents...
, for example bergamot
Bergamot
Bergamot may refer to:*The Bergamot orange*Monarda, genus of herbs of similar odor to the Bergamot orange; in particular**Monarda didyma, called Bergamot, Scarlet Beebalm, Scarlet Monarda, Oswego Tea, or Crimson Beebalm...
oil which is used in many perfumes and aromatherapy oils.
Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarin
Furanocoumarin
Furanocoumarins, or furocoumarins, are a class of organic chemical compounds produced by a variety of plants. They are biosynthesized partly through the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized by a coupling of dimethylallyl pyrophosphate and 7-hydroxycoumarin...
s. They consist of coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...
annulated with furan
Furan
Furan is a heterocyclic organic compound, consisting of a five-membered aromatic ring with four carbon atoms and one oxygen. The class of compounds containing such rings are also referred to as furans....
.
Biosynthesis
The biosynthetic pathway is a combination of the shikimate pathway, which produces umbelliferoneUmbelliferone
Umbelliferone, also known as 7-hydroxycoumarin, hydrangine, skimmetine, and beta-umbelliferone, is a widespread natural product of the coumarin family. It occurs in many familiar plants from the Apiaceae family such as carrot, coriander and garden angelica, as well plants from other families such...
, and the mevalonate pathway.
Synthesis of umbelliferone
Umbelliferone is a phenylpropanoidPhenylpropanoid
The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acid phenylalanine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of cinnamic acid, which is synthesized from phenylalanine in the first...
and as such is synthesized from L-phenylalanine, which in turn is produced via the shikimate pathway. Phenylalanine is lysated into cinnamic acid
Cinnamic acid
Cinnamic acid is a white crystalline organic acid, which is slightly soluble in water.It is obtained from oil of cinnamon, or from balsams such as storax. It is also found in shea butter and is the best indication of its environmental history and post-extraction conditions...
, followed by hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
by cinnamate 4-hydroxylase to yield 4-coumaric acid
Coumaric acid
Coumaric acid is a hydroxycinnamic acid, an organic compound that is a hydroxy derivative of cinnamic acid. There are three isomers, o-coumaric acid, m-coumaric acid, and p-coumaric acid, that differ by the position of the hydroxy substitution of the phenyl group...
. The 4-coumaric acid is again hydroxylated by cinnamate/coumarate 2-hydroxylase to yield 2,4-dihydroxy-cinnamic acid followed by a bond rotation of the unsaturated bond adjacent to the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
group. Finally an intramolecular attack from the hydroxyl group of C2' to the carboxylic acid group closes the ring and forms the lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
umbelliferone.
Synthesis of methoxsalen
Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate is an intermediate product of both mevalonic acid pathway and DOXP/MEP pathway. It is an isomer of isopentenyl pyrophosphate and exists in virtually all life forms...
(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. Another hydroxylation is catalyzed by psoralen synthase
Psoralen synthase
In enzymology, a psoralen synthase is an enzyme that catalyzes the chemical reaction-marmesin + NADPH + H+ + O2 \rightleftharpoons psoralen + NADP+ + acetone + 2 H2O...
to yield psoralen
Psoralen
Psoralen is the parent compound in a family of natural products known as furocoumarins. It is structurally related to coumarin by the addition of a fused furan ring, and may be considered as a derivative of umbelliferone...
. A third hydroxylation by the enzyme psoralen 8-monooxygenase yields xanthotoxol which is followed by a methylation via the enzyme xanthotoxol O-methyltransferase
Xanthotoxol O-methyltransferase
In enzymology, a xanthotoxol O-methyltransferase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are S-adenosyl methionine and xanthotoxol, whereas its two products are S-adenosylhomocysteine and O-methylxanthotoxol....
and S-adenosyl methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
to yield methoxsalen.
Risks and side effects
Patients with high blood pressure or a history of liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
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
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
s, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, and in rare cases insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
.
Cultural aspects
Author John Howard GriffinJohn Howard Griffin
John Howard Griffin was an American journalist and author much of whose writing was about racial equality. He is best known for darkening his skin and journeying through Louisiana, Mississippi, Alabama, and Georgia to experience segregation in the Deep South in 1959...
used the chemical to darken his skin in order to investigate racial segregation in the south. He wrote the non-fiction book Black Like Me about his experiences.
Some cologne/perfume contains bergamot oil as one of the ingredients (for the scent). People wearing the concoction on places where the skin receives UV radiation
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
was radiated by the sun noticed that their skin turned brownish at those spots (due to the phototoxic effects of methoxsalen present in the bergamot oil). Most modern formulations of perfumes containing bergamot are de-methoxsalenised.