Novel CYP26 inhibitors potentiate the effects of all-trans-retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis

Joachim Veit, N. Guilloteau, D. Mendes, Valérie De Glas, Benoît Balau, F. Astruc-Diaz, Yves Poumay, Philippe Diaz

Résultats de recherche: Contribution à un journalNuméro spécial

Résumé

Darier disease (DD) is a rare hereditary dominant human disorder characterized by warty papules and plaques in seborrheic areas of the skin. DD has a chronic course with frequent relapses while treatments often remain unsatisfactory. Retinoic Acid (RA) and its derivatives (retinoids) cause substantial clinical improvements in patients with DD. However, their use remains limited due to significant adverse effects. The endogenous concentration of RA is predominantly controlled via RA-inducible cytochrome P450 family 26 enzymes (CYP26), which inactivate RA by hydroxylation. As an alternative approach to therapeutic administration of retinoids, inhibition of CYP26 enzymes and thus of RA clearance represents an attractive strategy due to resulting elevated concentrations of endogenous RA. We previously designed and synthesized a CYP26A1/B1 dual inhibitor and inhibitors selective for either CYP26A1 or CYP26B1. In this study, we investigated the effects of RA alone or in combination with these CYP26 inhibitors on gene expression and on epidermal barrier using transepithelial electrical resistance (TEER), in reconstructed human epidermis (RHE) made of primary keratinocytes from either normal or DD patients. When the dual CYP26A1/B1 inhibitor was combined with RA (10-9 M), the TEER and the expression of differentiation markers were modulated similarly to the effects obtained with higher concentrations of RA. Our data revealed that dual selective inhibition of CYP26A1/B1 with our new compound DX308 potentiates the effect of RA at low concentration on RHE. Hence, the result of this study indicates that dual inhibition of CYP26A1 and B1 by DX308 may represent a promising therapeutic strategy for the treatment of DD with reduced retinoid-induced adverse effects.
langueAnglais
PagesS91
Nombre de pages1
journalThe journal of investigative dermatology
Volume137
Numéro5, Supplement 1
Les DOIs
étatPublié - mai 2017

Empreinte digitale

Darier Disease
Enzyme Inhibitors
Tretinoin
Keratinocytes
Epidermis
Cytochrome P-450 Enzyme System
Phenotype
Retinoids
Acoustic impedance
Electric Impedance
Enzymes
Cytochrome P450 Family 26
Hydroxylation
Differentiation Antigens
Therapeutics
Gene expression
Retinoic Acid 4-Hydroxylase
Skin

Citer ceci

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title = "Novel CYP26 inhibitors potentiate the effects of all-trans-retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis",
abstract = "Darier disease (DD) is a rare hereditary dominant human disorder characterized by warty papules and plaques in seborrheic areas of the skin. DD has a chronic course with frequent relapses while treatments often remain unsatisfactory. Retinoic Acid (RA) and its derivatives (retinoids) cause substantial clinical improvements in patients with DD. However, their use remains limited due to significant adverse effects. The endogenous concentration of RA is predominantly controlled via RA-inducible cytochrome P450 family 26 enzymes (CYP26), which inactivate RA by hydroxylation. As an alternative approach to therapeutic administration of retinoids, inhibition of CYP26 enzymes and thus of RA clearance represents an attractive strategy due to resulting elevated concentrations of endogenous RA. We previously designed and synthesized a CYP26A1/B1 dual inhibitor and inhibitors selective for either CYP26A1 or CYP26B1. In this study, we investigated the effects of RA alone or in combination with these CYP26 inhibitors on gene expression and on epidermal barrier using transepithelial electrical resistance (TEER), in reconstructed human epidermis (RHE) made of primary keratinocytes from either normal or DD patients. When the dual CYP26A1/B1 inhibitor was combined with RA (10-9 M), the TEER and the expression of differentiation markers were modulated similarly to the effects obtained with higher concentrations of RA. Our data revealed that dual selective inhibition of CYP26A1/B1 with our new compound DX308 potentiates the effect of RA at low concentration on RHE. Hence, the result of this study indicates that dual inhibition of CYP26A1 and B1 by DX308 may represent a promising therapeutic strategy for the treatment of DD with reduced retinoid-induced adverse effects.",
author = "Joachim Veit and N. Guilloteau and D. Mendes and {De Glas}, Val{\'e}rie and Beno{\^i}t Balau and F. Astruc-Diaz and Yves Poumay and Philippe Diaz",
year = "2017",
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doi = "10.1016/j.jid.2017.02.549",
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volume = "137",
pages = "S91",
journal = "The journal of investigative dermatology",
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Novel CYP26 inhibitors potentiate the effects of all-trans-retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis. / Veit, Joachim; Guilloteau, N.; Mendes, D.; De Glas, Valérie; Balau, Benoît; Astruc-Diaz, F.; Poumay, Yves; Diaz, Philippe.

Dans: The journal of investigative dermatology, Vol 137, Numéro 5, Supplement 1, 05.2017, p. S91.

Résultats de recherche: Contribution à un journalNuméro spécial

TY - JOUR

T1 - Novel CYP26 inhibitors potentiate the effects of all-trans-retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis

AU - Veit,Joachim

AU - Guilloteau,N.

AU - Mendes,D.

AU - De Glas,Valérie

AU - Balau,Benoît

AU - Astruc-Diaz,F.

AU - Poumay,Yves

AU - Diaz,Philippe

PY - 2017/5

Y1 - 2017/5

N2 - Darier disease (DD) is a rare hereditary dominant human disorder characterized by warty papules and plaques in seborrheic areas of the skin. DD has a chronic course with frequent relapses while treatments often remain unsatisfactory. Retinoic Acid (RA) and its derivatives (retinoids) cause substantial clinical improvements in patients with DD. However, their use remains limited due to significant adverse effects. The endogenous concentration of RA is predominantly controlled via RA-inducible cytochrome P450 family 26 enzymes (CYP26), which inactivate RA by hydroxylation. As an alternative approach to therapeutic administration of retinoids, inhibition of CYP26 enzymes and thus of RA clearance represents an attractive strategy due to resulting elevated concentrations of endogenous RA. We previously designed and synthesized a CYP26A1/B1 dual inhibitor and inhibitors selective for either CYP26A1 or CYP26B1. In this study, we investigated the effects of RA alone or in combination with these CYP26 inhibitors on gene expression and on epidermal barrier using transepithelial electrical resistance (TEER), in reconstructed human epidermis (RHE) made of primary keratinocytes from either normal or DD patients. When the dual CYP26A1/B1 inhibitor was combined with RA (10-9 M), the TEER and the expression of differentiation markers were modulated similarly to the effects obtained with higher concentrations of RA. Our data revealed that dual selective inhibition of CYP26A1/B1 with our new compound DX308 potentiates the effect of RA at low concentration on RHE. Hence, the result of this study indicates that dual inhibition of CYP26A1 and B1 by DX308 may represent a promising therapeutic strategy for the treatment of DD with reduced retinoid-induced adverse effects.

AB - Darier disease (DD) is a rare hereditary dominant human disorder characterized by warty papules and plaques in seborrheic areas of the skin. DD has a chronic course with frequent relapses while treatments often remain unsatisfactory. Retinoic Acid (RA) and its derivatives (retinoids) cause substantial clinical improvements in patients with DD. However, their use remains limited due to significant adverse effects. The endogenous concentration of RA is predominantly controlled via RA-inducible cytochrome P450 family 26 enzymes (CYP26), which inactivate RA by hydroxylation. As an alternative approach to therapeutic administration of retinoids, inhibition of CYP26 enzymes and thus of RA clearance represents an attractive strategy due to resulting elevated concentrations of endogenous RA. We previously designed and synthesized a CYP26A1/B1 dual inhibitor and inhibitors selective for either CYP26A1 or CYP26B1. In this study, we investigated the effects of RA alone or in combination with these CYP26 inhibitors on gene expression and on epidermal barrier using transepithelial electrical resistance (TEER), in reconstructed human epidermis (RHE) made of primary keratinocytes from either normal or DD patients. When the dual CYP26A1/B1 inhibitor was combined with RA (10-9 M), the TEER and the expression of differentiation markers were modulated similarly to the effects obtained with higher concentrations of RA. Our data revealed that dual selective inhibition of CYP26A1/B1 with our new compound DX308 potentiates the effect of RA at low concentration on RHE. Hence, the result of this study indicates that dual inhibition of CYP26A1 and B1 by DX308 may represent a promising therapeutic strategy for the treatment of DD with reduced retinoid-induced adverse effects.

U2 - 10.1016/j.jid.2017.02.549

DO - 10.1016/j.jid.2017.02.549

M3 - Special issue

VL - 137

SP - S91

JO - The journal of investigative dermatology

T2 - The journal of investigative dermatology

JF - The journal of investigative dermatology

SN - 0022-202X

IS - 5, Supplement 1

ER -