Use of human in Vitro skin models for accurate and ethical risk assessment: Metabolic considerations

Abstract

Several human skin models employing primary cells andimmortalized cell lines used as monocultures or combined toproduce reconstituted 3D skin constructs have been developed.Furthermore, these models have been included in European genotoxicityand sensitization/irritation assay validation projects.In order to help interpret data, Cosmetics Europe (formerlyCOLIPA) facilitated research projects that measured a variety ofdefined phase I and II enzyme activities and created a completeproteomic profile of xenobiotic metabolizing enzymes (XMEs) innative human skin and compared them with data obtained froma number of in vitro models of human skin. Here, we have summarizedour findings on the current knowledge of the metaboliccapacity of native human skin and in vitro models and made anoverall assessment of the metabolic capacity from gene expression,proteomic expression, and substrate metabolism data. The knownlow expression and function of phase I enzymes in native wholeskin were reflected in the in vitro models. Some XMEs in whole skinwere not detected in in vitro models and vice versa, and some majorhepatic XMEs such as cytochrome P450-monooxygenases wereabsent or measured only at very low levels in the skin. Conversely,despite varying mRNA and protein levels of phase II enzymes, functionalactivity of glutathione S-transferases, N-acetyltransferase 1,and UDP-glucuronosyltransferases were all readily measurable inwhole skin and in vitro skin models at activity levels similar to thosemeasured in the liver. These projects have enabled a better understandingof the contribution of XMEs to toxicity endpoints. © The Author 2013. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.