title: Ketoprofen-induced formation of amino acid photoadducts: possible explanation for photocontact allergy to ketoprofen.
abstract: Photocontact allergy is a well-known side effect of topical preparations of the nonsteroidal anti-inflammatory drug ketoprofen. Photocontact allergy to ketoprofen appears to induce a large number of photocross allergies to both structurally similar and structurally unrelated compounds. Contact and photocontact allergies are explained by structural modification of skin proteins by the allergen. This complex is recognized by the immune system, which initiates an immune response. We have studied ketoprofen's interaction with amino acids to better understand ketoprofen's photoallergenic ability. Irradiation of ketoprofen and amino acid analogues resulted in four different ketoprofen photodecarboxylation products (6-9) together with a fifth photoproduct (5). Dihydroquinazoline 5 was shown to be a reaction product between the indole moiety of 3-methylindole (Trp analogue) and the primary amine benzylamine (Lys analogue). In presence of air, dihydroquinazoline 5 quickly degrades into stable quinazolinone 12. The corresponding quinazolinone (17) was formed upon irradiation of ketoprofen and the amino acids N-acetyl-l-Trp ethyl ester and l-Lys ethyl ester. The formation of these models of an immunogenic complex starts with the ketoprofen-sensitized formation of singlet oxygen, which reacts with the indole moiety of Trp. The formed intermediate subsequently reacts with the primary amino functionality of Lys, or its analogue, to form a Trp-Lys adduct or a mimic thereof. The formation of a specific immunogenic complex that does not contain the allergen but that can still induce photocontact allergy would explain the large number of photocross allergies with ketoprofen. These allergens do not have to be structurally similar as long as they can generate singlet oxygen. To the best of our knowledge, there is no other suggested explanation for ketoprofen's photoallergenic properties that can account for the observed photocross allergies. The formation of a specific immunogenic complex that does not contain the allergen is a novel hypothesis in the field of contact and photocontact allergy.
authors.affiliation: Dermatochemistry and Skin Allergy, Department of Chemistry and Molecular Biology, University of Gothenburg , SE-412 96 Gothenburg, Sweden.
authors.forename: Isabella
authors.initials: I
authors.lastname: Karlsson
authors.forename: Elin
authors.initials: E
authors.lastname: Persson
authors.forename: Andreas
authors.initials: A
authors.lastname: Ekebergh
authors.forename: Jerker
authors.initials: J
authors.lastname: Mårtensson
authors.forename: Anna
authors.initials: A
authors.lastname: Börje
mesh_terms: D000596:Amino Acids / Q000528:radiation effects*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000528:radiation effects*; D017454:Dermatitis, Photoallergic / Q000209:etiology; D007660:Ketoprofen / Q000009:adverse effects / Q000528:radiation effects*; D010782:Photolysis; D014466:Ultraviolet Rays
chemical_list: D000596:Amino Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007660:Ketoprofen