Retinoic Acid and its 4-Oxo Metabolites are Functionally Active in Human Skin Cells In Vitro

• Published in: Journal of investigative dermatology Vol. 125; no. 1; pp. 143 - 153
• Main Authors: Baron, Jens M., Heise, Ruth, Blaner, William S., Neis, Mark, Joussen, Sylvia, Dreuw, Alexandra, Marquardt, Yvonne, Saurat, Jean-Hilaire, Merk, Hans F., Bickers, David R., Jugert, Frank K.
• Format: Journal Article
• Language: English
• Published: Danvers, MA Elsevier Inc 01-07-2005; Nature Publishing; Elsevier Limited
• Subjects: Biological and medical sciences; dermal fibroblasts; Dermatology; Electrophoresis, Gel, Two-Dimensional; epidermal keratinocytes; Fibroblasts - drug effects; Fibroblasts - metabolism; Fluorescent Antibody Technique; functional proteomics; gene expression profile; Gene Expression Regulation; Humans; In Vitro Techniques; Isotretinoin - metabolism; Keratinocytes - drug effects; Keratinocytes - metabolism; Male; Medical sciences; Oligonucleotide Array Sequence Analysis; Polymerase Chain Reaction; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tretinoin - analogs & derivatives; Tretinoin - metabolism; Tretinoin - pharmacology; dermal fibroblasts; gene expression profile; epidermal keratinocytes; functional proteomics; Human; Dermatology; Metabolite; Epidermis; In vitro; Gene expression profile; dermal fibroblasts/epidermal keratinocytes/functional proteomics/gene expression profile; Proteomics; Keratinocyte; Skin; Derm; Cell; Fibroblast; Retinoic acid
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1111/j.0022-202X.2005.23791.x

Retinoic acid exerts a variety of effects on gene transcription that regulate growth, differentiation, and inflammation in normal and neoplastic skin cells. Because there is a lack of information regarding the influence of metabolic transformation of retinoids on their pharmacologic effects in skin, we have analyzed the functional activity of all-trans-, 9-cis-, and 13-cis-retinoic acid and their 4-oxo-metabolites in normal human epidermal keratinocytes (NHEKs) and dermal fibroblasts using gene and protein expression profiling techniques, including cDNA microarrays, two-dimensional gel electrophoresis, and MALDI-MS. It was previously thought that the 4-oxo-metabolites of RA are inert catabolic end-products but our results indicate instead that they display strong and isomer-specific transcriptional regulatory activity in both NHEKs and dermal fibroblasts. Microarray and proteomic analyses identified a number of novel genes/gene products that are influenced by RA treatment of NHEKs or fibroblasts, including genes for enzymes catalyzing biotransformation of retinoids, corticosteroids, and antioxidants and structural and transport proteins known to be essential for homeostasis. Our results expand current knowledge regarding retinoic acid action within skin cells and the target tissue/cell regulatory systems that are important for modulating the physiological and pharmacological effects of this important class of dermatological drugs.