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Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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2009 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 160, no 1, 26-36 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866). OBJECTIVES: To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial. METHODS: Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1alpha and tumour necrosis factor-alpha]. RESULTS: Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected. CONCLUSIONS: Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.

Place, publisher, year, edition, pages
2009. Vol. 160, no 1, 26-36 p.
Keyword [en]
all-trans retinoic acid, CYP26 protein, cytokeratin, metabolism, skin
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97645DOI: 10.1111/j.1365-2133.2008.08895.xISI: 000261710800004PubMedID: 19016711OAI: oai:DiVA.org:uu-97645DiVA: diva2:172667
Available from: 2008-10-28 Created: 2008-10-28 Last updated: 2010-08-10Bibliographically 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.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 387
CYP, CYP26, retinoids, vitamin A, RAMBA, metabolism, keratinocyte, epidermis, retinoid regulated genes
National Category
Dermatology and Venereal Diseases
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
Available from: 2008-10-28 Created: 2008-10-28Bibliographically approved

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