Methoxsalen (or xanthotoxin) 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 coumarinannulated with furan. It can also be injected and used topically.
Umbelliferone is a phenylpropanoid 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 (umbellic 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.[10]
Risks and side effectsedit
Patients with high blood pressure or a history of liver 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, headaches, dizziness, and in rare cases insomnia.
Methoxsalen has also been classified as an IARC Group 1 carcinogen (known to cause cancer) but is only cancerous when combined with light - UVA radiation.[11]
Society and cultureedit
Author John Howard Griffin (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 (1961) about his experiences.[12]
^ ab"AusPAR: Methoxsalen". Therapeutic Goods Administration (TGA). 12 December 2019. Retrieved 17 September 2021.
^"FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
^"Uvadex- methoxsalen injection, solution". DailyMed. U.S. National Library of Medicine. Retrieved 17 September 2021.
^"Oxsoralen-Ultra- methoxsalen capsule, liquid filled". DailyMed. U.S. National Library of Medicine. Retrieved 17 September 2021.
^Fahmy IR, Abu-Shady H (1947). "Ammi majus Linn.; pharmacognostical study and isolation of a crystalline constituent, ammoidin". Quarterly Journal of Pharmacy and Pharmacology. 20 (3): 281–91, discussion 426. PMID 20273299.
^Marshall SR (June 2006). "Technology insight: ECP for the treatment of GvHD--can we offer selective immune control without generalized immunosuppression?". Nature Clinical Practice. Oncology. 3 (6). Nature Publishing: 302–314. doi:10.1038/ncponc0511. PMID 16757968. S2CID 8441159.
^Nielsen BE (1970). Coumarins of Umbelliferous plants. Copenhagen: Royal Danish School of Pharmacy. Cited by Mitchell and Rook (1979).
^Mitchell J, Rook A (1979). Botanical Dermatology: Plants and Plant Products Injurious to the Skin. Vancouver: Greengrass. pp. 692–699. ISBN978-0-88978-047-7.
^Dewick PM (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). John Wiley & Sons. pp. 161, 164–165.
^. American Cancer Society. Archived from the original on 30 September 2016.
^Mikkelson D (27 July 2003). "Death of John Howard Griffin". snopes.com. Snopes Media Group Inc.
methoxsalen, xanthotoxin, sold, under, brand, name, oxsoralen, among, others, medication, used, treat, psoriasis, eczema, vitiligo, some, cutaneous, lymphomas, conjunction, with, exposing, skin, ultraviolet, light, from, lamps, sunlight, modifies, skin, cells,. Methoxsalen or xanthotoxin 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 MethoxsalenClinical dataTrade namesOxsoralen Uvadex 8 mop othersOther namesxanthotoxinAHFS Drugs comConsumer Drug InformationLicense dataUS DailyMed MethoxsalenPregnancycategoryAU D 1 2 Routes ofadministrationExtracorporeal By mouthATC codeD05AD02 WHO D05BA02 WHO Legal statusLegal statusAU S4 Prescription only 1 2 US WARNING 3 Rx only 4 5 Pharmacokinetic dataElimination half life 2 hoursIdentifiersIUPAC name 9 methoxy 7H furo 3 2 g chromen 7 oneCAS Number298 81 7 YPubChem CID4114DrugBankDB00553 YChemSpider3971 YUNIIU4VJ29L7BQKEGGD00139 YChEBICHEBI 18358 YChEMBLChEMBL416 YNIAID ChemDB001590CompTox Dashboard EPA DTXSID8020830ECHA InfoCard100 005 516Chemical and physical dataFormulaC 12H 8O 4Molar mass216 192 g mol 13D model JSmol Interactive imageSMILES COc1c2c ccc O o2 cc3c1occ3InChI InChI 1S C12H8O4 c1 14 12 10 8 4 5 15 10 6 7 2 3 9 13 16 11 7 12 h2 6H 1H3 YKey QXKHYNVANLEOEG UHFFFAOYSA N Y verify Contents 1 Natural sources 2 Biosynthesis 2 1 Synthesis of umbelliferone 2 2 Synthesis of methoxsalen 3 Risks and side effects 4 Society and culture 5 ReferencesNatural sources editIn 1947 methoxsalen was isolated under the name ammoidin from the plant Ammi majus bishop s weed 6 7 In 1970 Nielsen extracted 8 methoxypsoralen from four species of the genus Heracleum in the carrot family Apiaceae 8 9 including Heracleum mantegazzianum and Heracleum sphondylium An additional 32 species of the genus Heracleum were found to contain 5 methoxypsoralen bergapten or other furanocoumarins Biosynthesis editThe biosynthetic pathway is a combination of the shikimate pathway which produces umbelliferone and the mevalonate pathway Synthesis of umbelliferone edit nbsp Umbelliferone Umbelliferone is a phenylpropanoid 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 umbellic 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 Synthesis of methoxsalen edit nbsp Dimethylallyl pyrophosphate 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 10 Risks and side effects editPatients with high blood pressure or a history of liver 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 headaches dizziness and in rare cases insomnia Methoxsalen has also been classified as an IARC Group 1 carcinogen known to cause cancer but is only cancerous when combined with light UVA radiation 11 Society and culture editAuthor John Howard Griffin 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 1961 about his experiences 12 References edit a b Uvadex Therapeutic Goods Administration TGA 13 December 2019 Retrieved 25 August 2020 a b AusPAR Methoxsalen Therapeutic Goods Administration TGA 12 December 2019 Retrieved 17 September 2021 FDA sourced list of all drugs with black box warnings Use Download Full Results and View Query links nctr crs fda gov FDA Retrieved 22 Oct 2023 Uvadex methoxsalen injection solution DailyMed U S National Library of Medicine Retrieved 17 September 2021 Oxsoralen Ultra methoxsalen capsule liquid filled DailyMed U S National Library of Medicine Retrieved 17 September 2021 Fahmy IR Abu Shady H 1947 Ammi majus Linn pharmacognostical study and isolation of a crystalline constituent ammoidin Quarterly Journal of Pharmacy and Pharmacology 20 3 281 91 discussion 426 PMID 20273299 Marshall SR June 2006 Technology insight ECP for the treatment of GvHD can we offer selective immune control without generalized immunosuppression Nature Clinical Practice Oncology 3 6 Nature Publishing 302 314 doi 10 1038 ncponc0511 PMID 16757968 S2CID 8441159 Nielsen BE 1970 Coumarins of Umbelliferous plants Copenhagen Royal Danish School of Pharmacy Cited by Mitchell and Rook 1979 Mitchell J Rook A 1979 Botanical Dermatology Plants and Plant Products Injurious to the Skin Vancouver Greengrass pp 692 699 ISBN 978 0 88978 047 7 Dewick PM 2009 Medicinal Natural Products A Biosynthetic Approach 3rd ed John Wiley amp Sons pp 161 164 165 Known and Probable Human Carcinogens American Cancer Society Archived from the original on 30 September 2016 Mikkelson D 27 July 2003 Death of John Howard Griffin snopes com Snopes Media Group Inc Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Methoxsalen amp oldid 1213639887, wikipedia, wiki, book, books, library,
