RETINOIC ACID RECEPTOR-GAMMA MEDIATES TOPICAL RETINOID EFFICACY AND IRRITATION IN ANIMAL-MODELS

Among retinoic acid receptors (RARs) alpha, beta, and gamma, the messe nger RNA level of RAR-gamma is the most readily detectable by Northern blotting in human and mouse skin. This observation suggests that RAR- gamma may play a critical role in the modulation of the therapeutic be nefits and side effects of retinoids in skin. To test this hypothesis, 11 RAR-gamma selective retinoids were synthesized based on three rela ted structures. Each compound was found to prefer RAR-gamma when asses sed by retinoid-induced transcriptional activity (RAR-gamma > RAR-beta > RAR-alpha). The apparent Kd for binding to recombinant receptor pro tein was found to follow a similar trend. To correlate this receptor s electivity with in vivo activity, the compounds were tested topically in the Rhino mouse utriculi reduction and rabbit irritation models, tw o assays widely used to screen retinoids for efficacy and side effects , respectively. The results indicated that for these compounds, both e fficacy in the utriculi reduction assay and irritation potential in ra bbits correlated positively with the RAR-gamma transactivation activit y, with r(2) of 0.9 and 0.8, respectively. These data suggest that RAR -gamma is an important regulator of retinoic acid efficacy in skin and further, that the irritation associated with the use of retinoids is most likely a receptor-mediated process.