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Both all-trans retinoic acid and cytochrome P450 (CYP26)  inhibitors affect the expression of vitamin A metabolizing enzymes and Retinoic biomarkers in organotypic epidermis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2009 (English)In: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 301, no 7, 475-485 p.Article in journal (Refereed) Published
Abstract [en]

The biosynthesis of retinoic acid (RA) from retinol is controlled by several enzymes, e.g. dehydrogenases (RalDH2, RoDH-4) and   retinol-esterifying enzyme (LRAT), whereas its degradation mainly   involves CYP26 enzymes. In keratinocytes, RA activates the nuclear   retinoid-receptors inducing the transcription of many genes. Here, we  examined the effects of RA and the CYP26 inhibitors, liarozole and talarozole, on retinoid metabolism and RA-regulated genes in organotypic epidermis. RA induced the expression of CYP26 enzymes   already after 8 h, whereas LRAT exhibited a later response and peaked   at 48 h, indicating a feedback induction of retinol esterification. In   line with a reduced biosynthesis of RA from retinol after exogenous RA,   the expression of RDH16 reduced 80% in response to exogenous RA. The   mRNA expression of RA-regulated genes (KRT2, KRT4, CRABPII and HBEGF)   was altered within 24 h after RA exposure. In contrast, the CYP26   inhibitors caused only minor effects, except for a clear-cut induction  of CYP26A1 only when combined with minute amounts of exogenous RA.   Cellular accumulation of exogenous [H-3]RA was higher after talarozole  than after liarozole, probably indicating a greater CYP26-inhibitory   potency of the former drug. The present study shows that CYP26A1  expression is extremely sensitive to both exogenous RA and increased   endogenous RA levels, i.e. due to CYP26 inhibition, and thus an excellent biomarker for retinoid signalling in organotypic epidermis.

Place, publisher, year, edition, pages
2009. Vol. 301, no 7, 475-485 p.
Keyword [en]
CYP26, RAMBA, Metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97647DOI: 10.1007/s00403-009-0937-7ISI: 000268510700001PubMedID: 19294396OAI: oai:DiVA.org:uu-97647DiVA: diva2:172669
Available from: 2008-10-28 Created: 2008-10-28 Last updated: 2017-12-14Bibliographically 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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