title: Effects of the genotoxic compounds, benzo[a]pyrene and cyclophosphamide on phase 1 and 2 activities in EpiDerm™ models.
abstract: The micronucleus assay in the 3D human reconstructed EpiDerm™ skin model (RSMN) is a promising new assay for evaluating genotoxicity of dermally applied chemicals.        To complement the testing of metabolically activated chemicals, such as cyclophosphamide (CPA) and benzo[a]pyrene (B[a]P), we measured phase 1 (ethoxyresorufin O-deethylation (EROD) and testosterone metabolism) and 2 activities (UGTs and GSTs) in non-treated and genotoxin treated EpiDerm™ models in a study design which mimics the RSMN assay. The assay involved a three-dose dosing regimen over 72 h to take into account effects e.g. enzyme induction, which requires longer than the standard 2 dose 48-h assay.        These studies demonstrated the presence of basal phase 1 and 2 activities of EpiDerm™ models.        With the exception of GST, all of the activities measured did not reproducibly change over time.        It was possible to measure enzyme induction using this assay design. EROD activity was significantly induced by B[a]P but not by CPA. CPA and B[a]P had little or no reproducible effects on GST and UGT activities.        In conclusion, a number of metabolic enzyme activities were present in the EpiDerm™ skin model and at least the CYP1 family was inducible.
authors.affiliation: Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Götz
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Hewitt
authors.forename: Erich
authors.initials: E
authors.lastname: Jermann
authors.forename: Julia
authors.initials: J
authors.lastname: Tigges
authors.forename: Zippora
authors.initials: Z
authors.lastname: Kohne
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hübenthal
authors.forename: Jean
authors.initials: J
authors.lastname: Krutmann
authors.forename: Hans F
authors.initials: HF
authors.lastname: Merk
authors.forename: Ellen
authors.initials: E
authors.lastname: Fritsche
mesh_terms: D000279:Administration, Cutaneous; D001564:Benzo(a)pyrene / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D015162:Micronucleus Tests; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000201:enzymology; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D009153:Mutagens; D001564:Benzo(a)pyrene; D003520:Cyclophosphamide; D013250:Steroid Hydroxylases; D019363:Cytochrome P-450 CYP1A1; C022657:steroid hormone 6-beta-hydroxylase; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase