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Oximes: metabolic activation and structure-allergenic activity relationships
Moa Andresen Bergström1, Sofia I Andersson, Kerstin Broo
1Department of Chemistry, Dermatochemistry and Skin Allergy, Medicinal Chemistry, Göteborg University, SE-412 96 Göteborg, Sweden.
Journal of Medicinal Chemistry
|March 29, 2008
Summary
Chemicals activating in the skin can cause allergic contact dermatitis. Structure-activity relationships reveal alpha,beta-unsaturation is key for oxime prohaptens, with steric hindrance reducing sensitization potential.
Area of Science:
- Dermatology
- Toxicology
- Biochemistry
Background:
- Metabolic activation of chemicals (prohaptens) in the skin is a known cause of allergic contact dermatitis.
- Understanding structure-allergenicity is crucial for assessing skin contact chemical safety.
Purpose of the Study:
- To explore structure-allergenic activity relationships for oxime prohaptens.
- To evaluate the utility of in vitro methods for predicting skin sensitization potential.
Main Methods:
- Utilized the local lymph node assay (LLNA) to assess sensitization capacity.
- Employed a glutathione (GSH) trapping screen with liver microsomes for in vitro analysis.
- Investigated seven potential oxime prohaptens.
Main Results:
- An alpha,beta-unsaturation in oximes is essential for prohapten activity.
- Increased steric hindrance around the double bond decreases sensitizing capacity.
- In vitro GSH trapping can distinguish sensitizing from non-sensitizing oximes via mono-oxidized GSH conjugates, though caution is advised due to alternative mechanisms.
Conclusions:
- Cutaneous bioactivation is a critical factor in the toxicity assessment of skin contact chemicals.
- Structure-activity relationships provide insights into the mechanism of oxime-induced allergic contact dermatitis.
- In vitro GSH trapping assays show promise for predicting skin sensitization but require careful interpretation.
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