Alpha-methylene-gamma-butyrolactones: versatile skin bioactive natural products.

Natural products containing an alpha-methylene-gamma-butyrolactone moiety, mainly of the sesquiterpene type, are widely observed in plants, which upon coming into contact with skin, will induce major skin toxicological side effects or phytodermatitis. Indeed two main dermatological pathologies have been associated with a skin exposure to molecules containing an alpha-methylene-gamma-butyrolactone moiety: allergic contact dermatitis (ACD) and chronic actinic dermatitis (CAD). ACD is an immunologically based disease resulting from modifications of epidermal proteins by sensitizers or haptens. Indeed, alpha-methylene-gamma-butyrolactones are highly electrophilic structures that can act as Michael acceptors towards nucleophilic residues of proteins. Cysteine and lysine are the most modified residues leading, in the case of enantiomerically pure lactones, to the formation of diastereomeric adducts. This chemical enantioselectivity induces an enantiospecificity of the allergic reaction, i.e., an individual sensitized to one enantiomer will not develop clinical symptoms when exposed to the other enantiomer and vice versa. Sesquiterpene lactones have been also associated with another pathology that involves UV irradiation and DNA modifications. Interestingly, it was found that alpha-methylene-gamma-butyrolactones, in addition to their electrophilic properties, were highly photoreactive molecules able to react with thymine/thymidine to form [2 + 2] photoadducts in very high yields. In all cases a syn regioselectivity was observed, probably associated with the polarization of the exomethylenic bond. This high photoreactivity of alpha-methylene-gamma-butyrolactones towards thymidine could be an explanation of the progressive evolution of allergic contact dermatitis towards chronic actinic dermatitis.

Is a low content in atranol/chloroatranol safe in oak moss-sensitized individuals?

BACKGROUND: Chloroatranol and atranol are degradation products of chloroatranorin and atranorin, respectively, and have been identified as important contact allergens in oak moss absolute (Evernia prunastri). OBJECTIVES: To investigate whether chemically modified extracts of oak moss produce positive patch test reactions in previously sensitized subjects. METHODS: A sample of oak moss was treated by a polymer-based method to reduce the content of the two main allergens, namely atranol and chloroatranol, from 3.4% to less than 75 p.p.m. and from 1.8% to less than 25 p.p.m., respectively. Fourteen subjects with positive reactions to oak moss from Trolab and/or Chemotechnique were patch tested to this sample, diluted 1% in petrolatum. RESULTS: The chemically modified sample reacted negatively in six but gave still positive reactions in eight subjects, with the same intensity as the commercially available oak moss patch test materials. CONCLUSIONS: Polymer-based treatment of oak moss extract reduces the allergenic elicitation potential in previously sensitized individuals only to a minor extent. The residual concentrations of atranol and chloroatranol being less than 75 p.p.m. and 25 p.p.m., respectively, are unsafe for the consumer.

Contact allergy to oak moss: search for sensitizing molecules using combined bioassay-guided chemical fractionation, GC-MS, and structure-activity relationship analysis.

In addition to pure synthetic fragrance materials several natural extracts are still in use in the perfume industry. Among them oak moss absolute, prepared from the lichen Evernia prunastri (L.) Arch., is considered a major contact sensitizer and is therefore included in the fragrance mix used for diagnosing perfume allergy. The process of preparing oak moss absolute has changed during recent years and, even though several potential sensitizers have been identified from former benzene extracts, its present constituents and their allergenic status are not clear. In the study reported here, we applied a method developed for the identification of contact allergens present in natural complex mixtures to oak moss absolute. The method is based on the combination of bioassay-guided chemical fractionation, gas chromatography-mass spectrometry analysis and structure-activity relationship studies. Our first results showed that atranol and chloroatranol, formed by transesterification and decarboxylation of the lichen depsides, atranorin and chloroatranorin, during the preparation of oak moss absolute, are strong elicitants in most patients sensitized to oak moss. Methyl-beta-orcinol carboxylate, a depside degradation product and the most important monoaryl derivative of oak moss from an olfactory standpoint, was also found to elicit a reaction in most patients.

Chloroatranol, an extremely potent allergen hidden in perfumes: a dose-response elicitation study.

Oak moss absolute is a long-known, popular natural extract widely used in perfumes. It is reported as the cause of allergic reactions in a significant number of those with perfume allergy. Oak moss absolute has been the target of recent research to identify its allergenic components. Recently, chloroatranol, a hitherto unknown fragrance allergen, was identified in oak moss absolute. The objective was to assess the clinical importance of chloroatranol as a fragrance allergen by characterizing its elicitation profile. 13 patients previously showing a positive patch test to oak moss absolute and chloroatranol were included, together with a control group of 10 patients without sensitization to either of the 2 materials. A serial dilution patch test was performed on the upper back with concentrations ranging from 200 to 0.0063 p.p.m. of chloroatranol in ethanol. Simultaneously, the participant performed an open test simulating the use of perfumes on the volar aspect of the forearms in a randomized and double-blinded design. A solution with 5 p.p.m. chloroatranol was used for 14 days, and, in case of no reaction, the applications were continued for another 14 days with a solution containing 25 p.p.m. All test subjects (13/13) developed an allergic reaction at the site of application of the solution containing chloroatranol. Among them, 12/13 (92%) gave a positive reaction to the 5 p.p.m. solution and 1 to 25 p.p.m. None of the controls reacted (P < 0.001). The use test was terminated at median day 4. The dose eliciting a reaction in 50% of the test subjects at patch testing was 0.2 p.p.m. In conclusion, the hidden exposure to a potent allergen widely used in perfumes has caused a highly sensitized cohort of individuals. Judged from the elicitation profile, chloroatranol is the most potent allergen present in consumer products today.