| | |  | | | | Record from Web of Science® | | | | | | |
| HUMAN SKIN LEVELS OF RETINOIC ACID AND CYTOCHROME P-450-DERIVED 4-HYDROXYRETINOIC ACID AFTER TOPICAL APPLICATION OF RETINOIC ACID INVIVO COMPARED TO CONCENTRATIONS REQUIRED TO STIMULATE RETINOIC ACID RECEPTOR-MEDIATED TRANSCRIPTION INVITRO |
|
|
| Author(s): DUELL EA, ASTROM A, GRIFFITHS CEM, CHAMBON P, VOORHEES JJ |
| Source: JOURNAL OF CLINICAL INVESTIGATION Volume: 90 Issue: 4 Pages: 1269-1274 Published: OCT 1992 |
| Times Cited: 100 References: 30 |
| Abstract: Metabolism of retinoic acid to a less active metabolite, 4-hydroxyretinoic acid, occurs via cytochrome P450 isozyme(s). Effect of a pharmacological dose of retinoic acid on the level of retinoic acid in skin and on cytochrome P450 activity was investigated. A cream containing 0.1% retinoic acid or cream alone was applied topically to adult human skin for four days under occlusion. Treated areas were removed by a keratome and a microsomal fraction was isolated from each biopsy. In vitro incubation of H-3-retinoic acid with microsomes from in vivo retinoic acid treated sites resulted in a 4.5-fold increase (P = 0.0001, n = 13) in its transformation to 4-hydroxyretinoic acid in comparison to in vitro incubations with microsomes from in vivo cream alone treated sites. This cytochrome P450 mediated activity was oxygen- and NADPH-dependent and was inhibited 68% by 5 muM ketoconazole (P = 0.0035, n = 8) and 51% by carbon monoxide (P = 0.02, n = 6). Cotransfection of individual retinoic acid receptors (RARs) or retinoid X receptor-alpha (RXR-alpha) and a chloramphenicol acetyl transferase (CAT) reporter plasmid containing a retinoic acid responsive element into CV-1 cells was used to determine the ED50 values for stimulation of CAT activity by retinoic acid and its metabolites. Levels of all trans and 13-cis RA in RA-treated tissues were greater than the ED50 values determined for all three RARs with these compounds. Furthermore, the level of all trans RA was greater than the ED50 for RXR-alpha whereas the 4-OH RA level was greater than the ED50 for RAR-beta and RAR-gamma but less than for RAR-alpha and RXR-alpha. These data suggest that there are sufficient amounts of retinoic acid in treated skin to activate gene transcription over both RARs and RXR-alpha.
|
| Document Type: Article |
| Language: English |
| Reprint Address: DUELL, EA (reprint author), UNIV MICHIGAN, MED CTR, DEPT DERMATOL, R6558 KRESGE I, BOX 0528, ANN ARBOR, MI 48109 USA |
Addresses:
1. FAC MED STRASBOURG, CNRS, U 184, INSERM, GENET MOLEC EUCARYOTES LAB, STRASBOURG, FRANCE |
| Publisher: ROCKEFELLER UNIV PRESS, 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 |
| Subject Category: Medicine, Research & Experimental |
| IDS Number: JU681 |
| ISSN: 0021-9738 |
|
| | | | | | | | | Record from Web of Science® | | | | | | | | | |