title: Use of human in vitro skin models for accurate and ethical risk assessment: metabolic considerations.
abstract: Several human skin models employing primary cells and immortalized cell lines used as monocultures or combined to produce reconstituted 3D skin constructs have been developed. Furthermore, these models have been included in European genotoxicity and sensitization/irritation assay validation projects. In order to help interpret data, Cosmetics Europe (formerly COLIPA) facilitated research projects that measured a variety of defined phase I and II enzyme activities and created a complete proteomic profile of xenobiotic metabolizing enzymes (XMEs) in native human skin and compared them with data obtained from a number of in vitro models of human skin. Here, we have summarized our findings on the current knowledge of the metabolic capacity of native human skin and in vitro models and made an overall assessment of the metabolic capacity from gene expression, proteomic expression, and substrate metabolism data. The known low expression and function of phase I enzymes in native whole skin were reflected in the in vitro models. Some XMEs in whole skin were not detected in in vitro models and vice versa, and some major hepatic XMEs such as cytochrome P450-monooxygenases were absent or measured only at very low levels in the skin. Conversely, despite varying mRNA and protein levels of phase II enzymes, functional activity of glutathione S-transferases, N-acetyltransferase 1, and UDP-glucuronosyltransferases were all readily measurable in whole skin and in vitro skin models at activity levels similar to those measured in the liver. These projects have enabled a better understanding of the contribution of XMEs to toxicity endpoints.
authors.affiliation: SWS, 64390 Erzhausen, Germany. nickyhewittltd@yahoo.co.uk
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Hewitt
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Edwards
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
authors.forename: Carsten
authors.initials: C
authors.lastname: Goebel
authors.forename: Pierre
authors.initials: P
authors.lastname: Aeby
authors.forename: Julia
authors.initials: J
authors.lastname: Scheel
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reisinger
authors.forename: Gladys
authors.initials: G
authors.lastname: Ouédraogo
authors.forename: Daniel
authors.initials: D
authors.lastname: Duche
authors.forename: Joan
authors.initials: J
authors.lastname: Eilstein
authors.forename: Alain
authors.initials: A
authors.lastname: Latil
authors.forename: Julia
authors.initials: J
authors.lastname: Kenny
authors.forename: Claire
authors.initials: C
authors.lastname: Moore
authors.forename: Jochen
authors.initials: J
authors.lastname: Kuehnl
authors.forename: Joao
authors.initials: J
authors.lastname: Barroso
authors.forename: Rolf
authors.initials: R
authors.lastname: Fautz
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfuhler
mesh_terms: D000826:Animal Testing Alternatives; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D040901:Proteomics; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000941:ethics / Q000379:methods; D012867:Skin / Q000187:drug effects* / Q000201:enzymology; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000378:metabolism / Q000633:toxicity*
chemical_list: D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System
keywords: Cosmetics Europe.; human 3D skin models; keratinocytes; phase I and II metabolism; proteomics