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Retinoid signaling in human epidermal keratinocytes: The importance of cytochrome P450 (CYP) 26 for retinoic acid metabolism
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
Manuscript (Other academic)
Identifiers
URN: urn:nbn:se:uu:diva-97648OAI: oai:DiVA.org:uu-97648DiVA: diva2:172670
Available from: 2008-10-28 Created: 2008-10-28 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Retinoic Acid Metabolism Blocking Agents and the Skin: In vivo and in vitro Studies of the Effects on Normal and Diseased Human Epidermis
Open this publication in new window or tab >>Retinoic Acid Metabolism Blocking Agents and the Skin: In vivo and in vitro Studies of the Effects on Normal and Diseased Human Epidermis
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Retinoic Acid Metabolism Blocking Agents (RAMBAs) increase the endogenous levels of all-trans retinoic acid (RA) by inhibiting CYP26 enzymes. Thus they are believed to mimic the effects of retinoid treatment. Their mechanism of action and effects on vitamin A metabolism in keratinocytes are however uncertain. To explore this and the function of CYP26 in human skin was the main purpose of the project.

The effects of two RAMBAs (talarozole and liarozole) on the expression of retinoid biomarkers in epidermis were studied in vivo and in vitro. Normal human skin (n=16) exposed to topical talarozole for 9 days showed similar response as previously reported for topical RA, even though no skin inflammation occurred. Lamellar ichthyosis patients (n=11) treated systemically with liarozole showed variable clinical improvement after 4 weeks with only mild effects on the retinoid biomarkers and the expression did not always correlate at the protein and mRNA levels. In these studies the proinflammatory transcripts IL-1α and TNFα were down-regulated by RAMBAs. In vitro, using an organotypic epidermis model we first studied how the RA metabolism was affected by adding RA and/or RAMBAs. We next examined the effects of the same agents on the expression of vitamin A metabolising enzymes in monolayer cultures of proliferating and differentiating keratinocytes. The results show among other things that CYP26 A1 and B1 are both involved in the catabolism of RA, and that talarozole potently increases the level of endogenous RA, primarily by inhibiting CYP26B1. However the drug´s biological effects cannot be solely attributed to increased RA levels.

In conclusion, RAMBAs are promising new drugs for treatment of skin disorders, but further studies on their mechanism of action are needed.

Place, publisher, year, edition, pages
Uppsala: Universitetsbiblioteket, 2008. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 387
Keyword
CYP, CYP26, retinoids, vitamin A, RAMBA, metabolism, keratinocyte, epidermis, retinoid regulated genes
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-9325 (URN)978-91-554-7310-5 (ISBN)
Public defence
2008-11-20, Enghoffsalen, Akademiska Sjukhuset, ing. 50, 09:15
Opponent
Supervisors
Available from: 2008-10-28 Created: 2008-10-28Bibliographically approved

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