title: Metabolism and biological activities of topical 4-oxoretinoids in mouse skin.
abstract: Retinoic acid mediates most of the biological actions of vitamin A. It is oxidized by CYP26A1 to 4-oxoretinoic acid, considered as an inactive catabolite of retinoic acid. However, in the light of studies reporting the presence of 4-oxoretinal or 4-oxoretinol as the predominant retinoids during morphogenesis, we analyzed the retinoid-like biological activity of these oxoretinoids in mouse skin in vivo. Topical 4-oxoretinal and 4-oxoretinol promoted significant epidermal hyperplasia and metaplasia in mouse tail. They induced a moderate response for epidermal inflammation, compared with retinal, whereas neither 4-oxoretinal nor 4-oxoretinol prevented menadione-induced epidermal lipid peroxidation, unlike retinal and retinol. As analyzed by quantitative PCR, 4-oxoretinal and 4-oxoretinol did not reproduce the significant increased expression of genes coding for keratin 4, amphiregulin, heparin-EGF and CYP26A1, that did induce retinal and retinol. However, both retinal and 4-oxoretinal significantly inhibited the lipopolysaccharide-induced maturation of human dendritic cells in vitro. As analyzed in vivo and in vitro, 4-oxoretinal and 4-oxoretinol were not converted into retinoic acid. We conclude that 4-oxoretinal and 4-oxoretinol exert a moderate direct retinoid-like activity in vivo, thus confirming previous in vitro studies in amphibians showing 4-oxometabolites of vitamin A as bioactive agents rather than inactive catabolites.
authors.affiliation: Department of Dermatology, University Hospital, Geneva, Switzerland. olivier.sorg@hcuge.ch
authors.forename: Olivier
authors.initials: O
authors.lastname: Sorg
authors.forename: Christian
authors.initials: C
authors.lastname: Tran
authors.forename: Pierre
authors.initials: P
authors.lastname: Carraux
authors.forename: Denise
authors.initials: D
authors.lastname: Grand
authors.forename: Christelle
authors.initials: C
authors.lastname: Barraclough
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Arrighi
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.forename: Vincent
authors.initials: V
authors.lastname: Piguet
authors.forename: Jean-Hilaire
authors.initials: JH
authors.lastname: Saurat
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D012172:Retinaldehyde / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012176:Retinoids / Q000494:pharmacology; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013623:Tail; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D012176:Retinoids; D014801:Vitamin A; C099660:4-oxoretinaldehyde; C041819:4-oxoretinol; D009195:Peroxidase; D012172:Retinaldehyde