RETINOIC ACID METABOLITES EXHIBIT BIOLOGICAL-ACTIVITY IN HUMAN KERATINOCYTES, MOUSE MELANOMA-CELLS AND HAIRLESS MOUSE SKIN IN-VIVO

Topical all-trans retinoic acid (RA) modulates growth and differentiat ion of skin and is used in the treatment of various dermatological dis orders. RA is metabolized to 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, which are believed to be markedly less active than RA. 3,4-didehydrore tinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is pr esent in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy R A, 4-oxo RA and 5,6-epoxy RA as assessed by three retinoid responsive systems relevant to skin. RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epo xy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stim ulating hormone-isobutylmethylxanthine-inducible tyrosinase activity i n Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respec tively, at 100 nM. Daily topical application of the retinoids to hairl ess mouse skin for 4 days resulted in dose-dependent changes in epider mal thickness and global histological score. The relative potencies of RA, ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA, as calculated by p arallel line assay, were 1.0, 0.60, 0.34, 0.29 and 0.18, respectively, for epidermal hyperplasia and 1.0, 0.78, 0.23, 0.14 and 0.08, respect ively, for global histological score. Interestingly, the compounds exh ibited a similar rank order of potency with respect to induction of ce llular retinoic acid binding protein-II mRNA. These data indicate that ddRA, 4-hydroxy RA, 4-oxo RA and 5,6-epoxy RA exhibit significant bio logical activity in human keratinocytes, mouse melanoma cells and mous e skin, but are in general less potent than RA. Therefore, the RA meta bolites have the potential to contribute, in part, to the observed cut aneous biologic effects of RA. Furthermore, ddRA and RA metabolites ma y play a role in the control of skin growth and differentiation.