title: Retinoic acid metabolites exhibit biological activity in human keratinocytes, mouse melanoma cells and hairless mouse skin in vivo.
abstract: Topical all-trans retinoic acid (RA) modulates growth and differentiation of skin and is used in the treatment of various dermatological disorders. 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-didehydroretinoic acid (ddRA) is a metabolite of 3,4-didehydroretinol which is present in skin. ddRA is biologically active and acts as a morphogen. We have determined the relative biological activity of ddRA, 4-hydroxy RA, 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-epoxy RA (10-100 nM) reduced epidermal transglutaminase activity in human keratinocytes to similar extents, and inhibited alpha-melanocyte-stimulating hormone-isobutylmethylxanthine-inducible tyrosinase activity in Cloudman S-91 mouse melanoma cells by 67, 39, 48, 51 and 19%, respectively, at 100 nM. Daily topical application of the retinoids to hairless mouse skin for 4 days resulted in dose-dependent changes in epidermal 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 parallel 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, respectively, for global histological score. Interestingly, the compounds exhibited a similar rank order of potency with respect to induction of cellular retinoic acid binding protein-II mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Dermatology, University of Michigan, Ann Arbor.
authors.forename: N J
authors.initials: NJ
authors.lastname: Reynolds
authors.forename: G J
authors.initials: GJ
authors.lastname: Fisher
authors.forename: C E
authors.initials: CE
authors.lastname: Griffiths
authors.forename: A
authors.initials: A
authors.lastname: Tavakkol
authors.forename: H S
authors.initials: HS
authors.lastname: Talwar
authors.forename: P E
authors.initials: PE
authors.lastname: Rowse
authors.forename: T A
authors.initials: TA
authors.lastname: Hamilton
authors.forename: J J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000328:Adult; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004817:Epidermis / Q000201:enzymology; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D008812:Mice, Hairless; D014442:Monophenol Monooxygenase / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D018168:Receptors, Retinoic Acid; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; C018058:5,6-epoxyretinoic acid; C002202:4-oxoretinoic acid; C064742:3,4-didehydroretinoic acid; D014212:Tretinoin; C019429:4-hydroxyretinoic acid; D014442:Monophenol Monooxygenase; D011503:Transglutaminases