Conflicts of interest M.C., M.B. and L.W. were employed by Barrier Therapeutics at the time of the study. B.S. is currently employed by Barrier Therapeutics.
Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis
Article first published online: 21 OCT 2008
© 2008 The Authors. Journal Compilation © 2008 British Association of Dermatologists
British Journal of Dermatology
Volume 160, Issue 1, pages 26–36, January 2009
How to Cite
Pavez Loriè, E., Cools, M., Borgers, M., Wouters, L., Shroot, B., Hagforsen, E., Törmä, H. and Vahlquist, A. (2009), Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis. British Journal of Dermatology, 160: 26–36. doi: 10.1111/j.1365-2133.2008.08895.x
Results from this study have previously been presented at the Annual Society for Investigative Dermatology Meeting, Chicago, IL, U.S.A., March 2006 and the FASEB Retinoid Meeting, Palm Springs, CA, U.S.A., June 2006.
- Issue published online: 15 DEC 2008
- Article first published online: 21 OCT 2008
- Accepted for publication 26 April 2008
- all-trans retinoic acid;
- CYP26 protein;
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.