1. ^*Department of Dermatology and Allergology, University Hospital of the RWTH, Aachen, Germany;
2. ^†Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA;
3. ^‡Institute of Biochemistry, University Hospital of the RWTH, Aachen, Germany;
4. ^§Department of Dermatology, Hôpital Cantonal University, Geneva, Switzerland;
5. ^¶Department of Dermatology, Columbia University, College of Physicians and Surgeons, New York, New York, USA

Correspondence: PD Dr med Jens Malte Baron, Department of Dermatology, University Hospital RWTH Aachen, Pauwelsstrae 30, D-52074 Aachen, Germany. Email: JensMalte.Baron@post.rwth-aachen.de

¹Both authors contributed equally to this work.

Received 7 September 2004; Revised 27 January 2005; Accepted 8 February 2005.

Abstract

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.