Metabolically competent human skin models: activation and genotoxicity of benzo[a]pyrene
| Autor: | Andreas Luch, Christoph Hutzler, Udo Bock, Susanne Trappe, Joep Brinkmann, Timo Otter, Kristin Stolpmann, Frank Henkler, Manfred Liebsch, Doris Genkinger |
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| Rok vydání: | 2012 |
| Předmět: |
Stereochemistry
Human skin Toxicology medicine.disease_cause Models Biological skin models chemistry.chemical_compound Tandem Mass Spectrometry medicine Benzo(a)pyrene Skin equivalent Humans comet assay Carcinogen Biotransformation Cells Cultured Skin integumentary system Chemistry Mutagenicity Tests benzo[a]pyrene primary normal human epidermal keratinocytes medicine.disease Molecular biology Comet assay medicine.anatomical_structure Skin cancer human skin Keratinocyte metabolism Genotoxicity Chromatography Liquid Mutagens Research Article |
| Zdroj: | Toxicological Sciences |
| ISSN: | 1096-0929 |
| Popis: | The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene (BP) is metabolized into a complex pattern of BP derivatives, among which the ultimate carcinogen (+)-anti-BP-7,8-diol-9,10-epoxide (BPDE) is formed to certain extents. Skin is frequently in contact with PAHs and data on the metabolic capacity of skin tissue toward these compounds are inconclusive. We compared BP metabolism in excised human skin, commercially available in vitro 3D skin models and primary 2D skin cell cultures, and analyzed the metabolically catalyzed occurrence of seven different BP follow-up products by means of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). All models investigated were competent to metabolize BP, and the metabolic profiles generated by ex vivo human skin and skin models were remarkably similar. Furthermore, the genotoxicity of BP and its derivatives was monitored in these models via comet assays. In a full-thickness skin, equivalent BP-mediated genotoxic stress was generated via keratinocytes. Cultured primary keratinocytes revealed a level of genotoxicity comparable with that of direct exposure to 50-100 nM of BPDE. Our data demonstrate that the metabolic capacity of human skin ex vivo, as well as organotypic human 3D skin models toward BP, is sufficient to cause significant genotoxic stress and thus cutaneous bioactivation may potentially contribute to mutations that ultimately lead to skin cancer. |
| Databáze: | OpenAIRE |
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