A hapten causing allergic contact dermatitis binds covalently to macromolecules via nucleophilic-electrophilic reactions or radical couplings. A prohapten can be seen as a chemically inert compound without electrophilic or radical forming properties. To exert its activity, the prohapten is activated, for example, metabolically, to the hapten. We have investigated the contact allergenic properties of a diene, (5R)-5-isopropenyl-2-methyl-1-methylene-2-cyclohexene (1), as a potential prohapten, and we found it to be a sensitizer in animal studies. The activity is likely to be exerted via epoxide metabolites. Thus, two potential metabolites of the investigated diene, (4S)-1,2-epoxy-4-isopropenyl-1-methyl-6-methylene-cyclohexane (3) and (7R)-7-isopropenyl-4-methyl-1-oxa-spiro[2.5]oct-4-ene (4), were synthesized and subjected to animal tests. Both epoxides were sensitizers. They also elicited significant reactions when tested in animals induced with 1, which indicates that they are formed from the diene in the skin. Furthermore, incubation of 1 with human liver microsomes produced both epoxides. The chemical reactivity of 1, 3, and 4 was investigated in relation to a hexapeptide, H-Pro-His-Cys-Lys-Arg-Met-OH. No adducts were obtained from reactions between the peptide and 1. However, epoxide 3 bound covalently to the cysteine residue and epoxide 4 to both the cysteine and proline residues. Since it is possible to relate the sensitizing capacity of a compound to its key physicochemical properties, knowledge-based expert systems have been developed to predict the toxicity of novel compounds by comparing the structure with activity data stored in the computer database. A diene related to 1 found in the knowledge-based expert system DEREK was considered as a nonsensitizer by this system. Our study indicates that conjugated dienes can be metabolized to contact allergens in the skin. Thus, when constructing predictive test methods based on SARs, it is important to analyze not only the virtual chemical structure of a compound but also its ability to act as a prohapten.
In the present study, the mechanism for the antigen formation of alpha, beta-unsaturated ketones was investigated. A series of analogues of carvone ((5R)-5-isopropenyl-2-methyl-2-cyclohexenone) with altered chemical reactivity and with retained overall structure or with retained reactivity and altered three-dimensional structure were synthesized. These analogues were tested for cross-reactivity in carvone-sensitized animals. Cross-reactivity was observed for analogue 3 ((5R)-5-isopropyl-2-methyl-2-cyclohexen-1-one). No cross-reactions were observed for analogues 1 ((2R,5R)-5-isopropenyl-2-methyl cyclohexanone) and 4 ((5R)-2,3-dimethyl-5-isopropenyl-2-cyclohexene-1-one). Both those compounds also failed to induce sensitization. These findings demonstrate that alpha, beta-unsaturated ketones form antigens after a nucleophilic attack at the beta-carbon with soft nucleophiles such as thiol in cysteine and not with the formation of a Schiff's base after a nucleophilic attack at the carbonyl carbon with nitrogen nucleophiles. Furthermore, no cross-reactivity was observed between R- and S-carvone indicating the importance of the 3-dimensional structure of haptens (and antigens) in T-cell recognition. The analogues were also tested for cross-reactivity on patients allergic to carvone. The results from the animal study were confirmed.
We have previously reported a reduction of sensitization to carvone in guinea pigs when adding non-allergenic, structurally related compounds simultaneously at induction. This study investigates the criteria needed to obtain a reduction of sensitization in contact allergy. Linalool, a non-sensitizer structurally unrelated to carvone, significantly reduced the sensitizing capacity of carvone in guinea pigs. The effect of different concentrations of inhibitors in mixtures with carvone was investigated. No significant differences in response were obtained between the concentrations explored. A possible anti-inflammatory effect from the inhibitory chemicals was investigated in vitro. No suppression of the immune system was seen. This study shows that a non-allergenic compound with a structure not resembling the hapten can reduce the sensitizing effect of the hapten. It indicates that reduction of an allergenic effect might occur in consumer products that are mixtures of different chemicals. Further studies with chemically unrelated compounds with and without allergenic effect are needed.
Endo-maleopimaric acid (MPA) is a contact allergen formed when colophonium is "modified" with maleic anhydride or fumaric acid. Previous patch testing showed a higher allergic response to petrolatum (pet.) preparations of MPA in amorphous form compared to MPA in crystalline form. In the present study, the impact of the physical form of MPA on the allergic response was investigated. Since the amorphous form is difficult to standardize, crystalline MPA mechanically incorporated or dissolved in pet. was used. A lower eliciting capacity was obtained from crystalline MPA, compared to that obtained from dissolved MPA, in guinea pigs intradermally induced with MPA. Using 3H-MPA a 3X difference in the dissolution into synthetic sweat from MPA dissolved in pet., compared to MPA mechanically incorporated, was demonstrated. A difference in bio-availability between dissolved and crystalline MPA could therefore be assumed. Crystalline MPA had a low sensitizing capacity compared to that seen for amorphous MPA in previous studies. The amorphous form of MPA is likely to have a larger surface area than crystalline MPA, with less ordered molecules, resulting in a higher dissolution rate and a greater bio-availability. Modified colophonium exists as amorphous solids and as viscous liquids. Thus, exposure will probably be to non-crystalline MPA and cases of contact allergy could be overlooked when screening with crystalline MPA.
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