Journal of Medicinal Chemistry 2008-04-24

Oximes: metabolic activation and structure-allergenic activity relationships.

Moa Andresen Bergström, Sofia I Andersson, Kerstin Broo, Kristina Luthman, Ann-Therese Karlberg

Index: J. Med. Chem. 51 , 2541-50, (2008)

Full Text: HTML

Abstract

Metabolic activation of chemicals (prohaptens) in the skin can cause allergic contact dermatitis. We have explored structure-allergenic activity relationships for seven potential oxime prohaptens using the local lymph node assay and a GSH trapping screen with liver microsomes. The general structure-allergenic activity relationships found were that an alpha,beta-unsaturation is necessary for an oxime to be a prohapten and that increased steric hindrance around this double bond leads to reduction in sensitizing capacity. We also found that sensitizing oximes can be distinguished in vitro from nonsensitizers by monitoring of mono-oxidized (+16 Da) GSH conjugates in the GSH trapping screen. However, care should be taken when interpreting data from GSH trapping screens, as nonsensitizers may also form GSH conjugates via alternative mechanisms. This investigation emphasizes the importance of considering cutaneous bioactivation in toxicity assessment of chemicals used in contact with the skin.