S10/L3 - Risk assessment and immunotoxicity

Abstract

It has been proposed that RARγ, the major retinoic acid receptor (RAR) subtype in skin, mediates retinoid-induced skin irritation. However, RARα is also found in skin, and its role in retinoid-induced skin irritation has not been tested. In this study, RAR subtype-specific agonists and antagonists were used to test the possible contribution of RARα to retinoid-induced skin irritation. Female hairless mice were treated topically on the dorsal skin for 5 days with various retinoids over a 2-log dose range, and cutaneous toxicity was scored by semiquantitative visual observations of skin flaking and abrasions daily up to 3 days post-treatment. Three RARα-selective agonists were ≥ 100-fold less potent as skin irritants than the structurally-related RAR pan-agonist, TTNPB. Skin irritation potency decreased in the following order: TTNPB > >Am580 > AGN 193835 > > 193836 and correlated with RARβ and/or RARγ binding affinity rather than RARα binding affinity. TTNPB-induced skin irritation was blocked in a dose-dependent fashion by co-treatment with the RAR pan-antagonist AGN 193109 but was not blocked by co-treatment with the RARα-specific antagonist AGN 194301. In contrast, skin irritation induced by the RARα-selective agonist AGN 193835 was almost completely blocked by co-treatment with AGN 193644, an RAR β/gg-selective antagonist. These data demonstrate that RARα is not significantly involved in mediating retinoid-induced skin irritation in mice and suggest that RARα-selective agonists may have reduced mucocutaneous side effects relative to other retinoids.