Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis

Loriè, Elizabeth Pavez; Cools, Martine; Borgers, M.; Wouters, Luc; Shroot, Braham; Hagforsen, Eva; Törmä, Hans; Vahlquist, Anders

doi:10.1111/j.1365-2133.2008.08895.x

Cited by 31 publications

(23 citation statements)

References 47 publications

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“…Topical treatment with talarozole did not result in skin inflammation or epidermal thickness as is often seen with topical retinoid treatment. When mRNA expression levels were examined in treated skin, talarozole increased the expression of CRABP2 , KRT4 , CYP26A1 and CYP26B1 dose dependently [140]. When protein expression levels were examined using immunofluorescence analysis, KRT4 protein levels were increased consistent with the mRNA expression data [140].…”

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 74%

“…When mRNA expression levels were examined in treated skin, talarozole increased the expression of CRABP2 , KRT4 , CYP26A1 and CYP26B1 dose dependently [140]. When protein expression levels were examined using immunofluorescence analysis, KRT4 protein levels were increased consistent with the mRNA expression data [140]. However, using both immunofluorescence analysis and Western blot analysis, there was no significant change in CYP26A1 or CYP26B1 protein expression following topical treatment with talarozole [140].…”

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 93%

“…They were increased but within normal or slightly above normal biological range and returned to baseline levels once talarozole was cleared from the body [138]. A phase I clinical trial was conducted to examine the use of talarozole as a topical treatment [140]. Topical treatment with talarozole did not result in skin inflammation or epidermal thickness as is often seen with topical retinoid treatment.…”

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 99%

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Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Nelson¹,

Buttrick²,

Isoherranen³

2013

CTMC

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Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity, and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.

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Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 74%

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 93%

Section: Pharmacological Effects Of Inhibitors Of Retinoic Acid Hymentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Nelson¹,

Buttrick²,

Isoherranen³

2013

CTMC

View full text Add to dashboard Cite

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“…Human CYP26C1 is highly expressed in testis and spleen [213]. All 3 human CYP26 members are found in skin [214].…”

Section: Cyp24a Cyp26a Cyp26b Cyp26c and Cyp27b Subfamiliesmentioning

confidence: 99%

“…Retinoic acid is a vitamin A-derived potent signaling molecule that is essential for a wide variety of biological processes including normal vertebrate embryonic development, and regulation of gene transcription and the cell cycle. Endogenous levels of retinoic acid are tightly regulated by biosynthetic enzymes and by catabolic CYP26 enzymes that convert the retinoid to less active and more readily excretable polar metabolites [210][211][212][213][214]355] (see review [398]). …”

Section: Cyp Enzymes In Families 5 To 51mentioning

confidence: 99%

Expression, Function and Regulation of Mouse Cytochrome P450 Enzymes: Comparison With Human Cytochrome P450 Enzymes

Hrycay

Bandiera

2009

CDM

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The present review focuses on the expression, function and regulation of mouse cytochrome P450 (Cyp) enzymes. Information compiled for mouse Cyp enzymes is compared with data collected for human CYP enzymes. To date, approximately 40 pairs of orthologous mouse-human CYP genes have been identified that encode enzymes performing similar metabolic functions. Recent knowledge concerning the tissue expression of mouse Cyp enzymes from families 1 to 51 is summarized. The catalytic activities of microsomal, mitochondrial and recombinant mouse Cyp enzymes are discussed and their involvement in the metabolism of exogenous and endogenous compounds is highlighted. The role of nuclear receptors, such as the aryl hydrocarbon receptor, constitutive androstane receptor and pregnane X receptor, in regulating the expression of mouse Cyp enzymes is examined. Targeted disruption of selected Cyp genes has generated numerous Cyp null mouse lines used to decipher the role of Cyp enzymes in metabolic, toxicological and biological processes. In conclusion, the laboratory mouse is an indispensable model for exploring human CYP-mediated activities.

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Topical Drug Candidate Selection Criteria and Cascade

Trottet

Maibach

2017

Dermal Drug Selection and Development

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Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression of retinoid-regulated genes in normal human epidermis

Abstract: 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.

Cited by 31 publications

References 47 publications

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Therapeutic Potential of the Inhibition of the Retinoic Acid Hydroxylases CYP26A1 and CYP26B1 by Xenobiotics

Expression, Function and Regulation of Mouse Cytochrome P450 Enzymes: Comparison With Human Cytochrome P450 Enzymes

Topical Drug Candidate Selection Criteria and Cascade

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