Photoisomerization of Tricyclo[5.2.1.0 4.10 ]deca‐2,5,8‐triene (Triquinacene)

Persson

Ekebergh

et al. 2014

Chem. Res. Toxicol.

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.

Section: ■ Experimental Proceduresmentioning

confidence: 99%

Ketoprofen-Induced Formation of Amino Acid Photoadducts: Possible Explanation for Photocontact Allergy to Ketoprofen

Persson

Ekebergh

et al. 2014

Chem. Res. Toxicol.

“…Column chromatographic separations were performed using Merck silica gel Geduran Si 60 (0.063–0.200 mm) and Sigma–Aldrich hexane mixture of isomers (bp 68–70°C). Photolysis reactions were performed in a falling film photoreactor, according to Professor de Meijere (12) with forced liquid circulation, purchased from NORMAG Labor‐ und Prozesstechnik. The photoreactor was equipped with a medium pressure mercury UV lamp (700 W, Heraeus, TQ 718, Z4 doped) as irradiation source.…”

mentioning

confidence: 99%

Investigation of the Sunscreen Octocrylene’s Interaction with Amino Acid Analogs in the Presence of UV Radiation

Photochem & Photobiology

Persson

Mårtensson

et al. 2012

Octocrylene is an organic UV filter, commonly used in sunscreens and cosmetics, which can give rise to both contact and photocontact allergy. Our aim was to investigate octocrylene's interaction with amino acid analogs in the presence of UV radiation to better understand the reason for octocrylene's photoallergenic capacity. The amino acid analogs were photolysed in presence and absence of octocrylene for 1 h in cyclohexane. The rate of degradation was considerably slower for all amino acid analogs when octocrylene was present in the mixture. Benzylamine, the lysine analog, did react with octocrylene during the photolysis and the corresponding amide was formed in an acylation reaction. By varying the benzylamine concentration and keeping the octocrylene concentration fixed the reaction rate was shown to be independent of the amine concentration. The same type of acylation reaction took place when octocrylene alone was photolysed in ethanol in which the ethyl ester was formed from octocrylene and ethanol. Our results suggest that octocrylene's ability to cause photocontact allergy could be due to its photoinduced reactivity toward primary amines and alcohols.

“…Photolysis reactions were performed in a falling film photoreactor, according to Professor de Meijere with forced liquid circulation, purchased from NORMAG Labor- und Prozesstechnik. The photoreactor was equipped with a medium pressure mercury UV lamp (700 W, Heraeus, TQ 718, Z4 doped) as an irradiation source.…”

Section: Methodsmentioning

confidence: 99%

Photodegradation of Dibenzoylmethanes: Potential Cause of Photocontact Allergy to Sunscreens

Hillerström

Stenfeldt

et al. 2009

Chem. Res. Toxicol.

One of the most frequently observed photoallergens today is the sunscreen agent 4-tert-butyl-4'-methoxy dibenzoylmethane (1a). The structurally similar compound, 4-isopropyldibenzoylmethane (1b), was a common cause of sunscreen allergy in the eighties and early nineties but was removed from the market in 1993 and replaced with dibenzoylmethane 1a. We have studied the photodegradation of the dibenzoylmethane 1a, to better understand how these substances cause an immune reaction. Several expected degradation products were formed and identified. Of these, arylglyoxals and benzils were of particular interest because they were unexplored as potential contact allergens. The allergenic potential of photodegraded 1a was evaluated by screening the formed arylglyoxals and benzils for their sensitizing capacity in the murine local lymph node assay. The arylglyoxals were found to be strong sensitizers. They were also found to be highly reactive toward the nucleophile arginine, which indicates that the immunogenic hapten-protein complex could be formed via an electrophilic-nucleophilic pathway. By varying the electron-withdrawing or -donating capacity of the substituent in the para position of the arylglyoxal, the electronic effects were shown to have no significant impact on either the sensitizing or the electrophilic power of arylglyoxals. Thus, a change in the substitution pattern of the parent dibenzoylmethane will not influence the sensitizing capacity of the products formed from them upon photodegradation. Furthermore, the combined studies of benzils, using the local lymph node assay and a cell proliferation assay, indicate that the benzils are cytotoxic rather than allergenic. Taken together, this study presents strong indication that photocontact allergy to dibenzoylmethanes is caused by the arylglyoxals that are formed upon photodegradation.