Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles

Daniel Bacqueville (1) , Carine Jacques (1) , Laure Duprat (1) , Emilien L. Jamin (2) , Beatrice Guiraud (1) , Elisabeth Perdu (3) , Sandrine Bessou-Touya (1) , Daniel Zalko (4) , Hélène Duplan (1)

1 Laboratoire de Pharmacochimie Pierre Fabre Dermo-Cosmétique
2 E20 - MetaToul AXIOM
3 ToxAlim - ToxAlim
4 ToxAlim-MeX - Métabolisme et Xénobiotiques

In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and β-naphthoflavone (βNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.

Mots clés: reconstructed human epidermis; hair follicle; cutaneous metabolism; gene expression; functional activity; coat; human health

Mots clés: épiderme; tissu cutané; dermatologie; peau; cheveu; santé humaine; enzyme du métabolisme des xénobiotiques; expression des gènes

Domaines: Sciences du Vivant [q-bio]

Daniel Bacqueville, Carine Jacques, Laure Duprat, Emilien L. Jamin, Beatrice Guiraud, et al.. Characterization of xenobiotic metabolizing enzymes of a reconstructed human epidermal model from adult hair follicles. Toxicology and Applied Pharmacology, 2017, 329, pp.190-201. ⟨10.1016/j.taap.2017.05.040⟩. ⟨hal-01608588⟩