Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis
| Autor: | Anders Vahlquist, Hans Törmä, M. Cools, Luc Wouters, B. Shroot, E. Pavez Loriè, Eva Hagforsen, M. Borgers |
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| Rok vydání: | 2008 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent medicine.drug_class Receptors Retinoic Acid Administration Topical Retinoic acid Gene Expression Dermatology Biology Proinflammatory cytokine chemistry.chemical_compound CYP26A1 Retinoids Young Adult Downregulation and upregulation Cytochrome P-450 Enzyme System Double-Blind Method Tretinoin Internal medicine medicine Cytochrome P-450 Enzyme Inhibitors Humans Retinoid Benzothiazoles RNA Messenger Cell Proliferation Analysis of Variance integumentary system Dose-Response Relationship Drug Retinol Retinal Dehydrogenase Middle Aged Retinoic Acid 4-Hydroxylase Triazoles Immunohistochemistry Endocrinology chemistry CYP2S1 Female Epidermis Biomarkers medicine.drug |
| Zdroj: | The British journal of dermatology. 160(1) |
| ISSN: | 1365-2133 |
| Popis: | Summary 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)-1α and tumour necrosis factor-α]. Results Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1α 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. |
| Databáze: | OpenAIRE |
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