title: Retinoic acid isomers applied to human skin in vivo each induce a 4-hydroxylase that inactivates only trans retinoic acid.
abstract: Application of all-trans retinoic acid to human skin for 4 d under occlusion produces a marked increase in retinoic acid 4-hydroxylase activity. In this study, the possible induction of other hydroxylase in response to 9-cis and 13-cis retinoic acid application to adult human skin in vivo was determined. Application of 0.1% all-trans, 0.1% 9-cis, and 0.1% 13-cis retinoic acid to human skin for 2 d resulted in induction of only all-trans retinoic acid 4-hydroxylase activity. The 4-hydroxylase activity in microsomes from the treated tissue ranged from 838 +/- 46 to 531 +/- 59 pg of 4- hydroxy all-trans retinoic acid formed/min/mg protein (n=6). These same preparations were unable to use 9-cis or 13-cis retinoic acid as substrate for the hydroxylation reaction. Extraction of the retinoic acid isomers from epidermis 48 h after application of 0.1% solution of each isomer yielded significant amounts of all-trans retinoic acid (36-72%) regardless of the isomer applied. The all-trans isomer produced by isomerization of both 9-cis and 13-cis retinoic acids is the likely inducer of the 4-hydroxylase. All-trans retinol and all-trans retinal were unable to compete with all-trans retinoic acid as substrate for 4-hydroxylase enzyme. The 4-hydroxylase induced in response to pharmacological doses of retinoic acids is specific for the all-trans isomer. The inability of 9-cis or 13-cis retinoic acid to induce their own hydroxylation and inactivation or act as substrate for the 4-hydroxylase in skin may have considerable implications in light of the clinical use of retinoids in the treatment of various diseases including cancers.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109-0528, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Duell
authors.forename: S
authors.initials: S
authors.lastname: Kang
authors.forename: J J
authors.initials: JJ
authors.lastname: Voorhees
mesh_terms: D000287:Administration, Topical; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D015474:Isotretinoin / Q000494:pharmacology; D008861:Microsomes / Q000201:enzymology; D000072516:Retinoic Acid 4-Hydroxylase; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D013997:Time Factors; D014212:Tretinoin / Q000494:pharmacology*; D014801:Vitamin A / Q000008:administration & dosage
chemical_list: D014801:Vitamin A; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase; D015474:Isotretinoin