Retinoic acid receptor gamma mediates topical retinoid efficacy and irritation in animal models

Abstract

Among retinoic acid receptors (RARs) α, β, and γ, the messenger RNA level of RAR-γ is the most readily detectable by Northern blotting in human and mouse skin. This observation suggests that RAR-γ may play a critical role in the modulation of the therapeutic benefits and side effects of retinoids in skin. To test this hypothesis, 11 RAR-γ selective retinoids were synthesized based on three related structures. Each compound was found to prefer RAR-γ when assessed by retinoid-induced transcriptional activity (RAR-γ RAR-β > RAR-α. The apparent K(d) for binding to recombinant receptor protein was found to follow a similar trend. To correlate this receptor selectivity with in vivo activity, the compounds were tested topically in the Rhino mouse utriculi reduction and rabbit irritation models, two assays widely used to screen retinoids for efficacy and side effects, respectively. The results indicated that for these compounds, both efficacy in the utriculi reduction assay and irritation potential in rabbits correlated positively with the RAR-γ transactivation activity, with r2 of 0.9 and 0.8, respectively. These data suggest that RAR-γ 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.