Biotransformation of 2,4-toluenediamine in human skin and reconstructed tissues.
Reconstructed human epidermis (RHE) is used for risk assessment of chemicals and cosmetics and RHE as well as reconstructed human full-thickness skin (RHS) become important for e.g., the pre-clinical development of drugs. Yet, the knowledge regarding their biotransformation capacity is still limited, although the metabolic activity is highly relevant for skin sensitization, genotoxicity, and the efficacy of topical dermatics. The biotransformation of the aromatic amine 2,4-toluenediamine (2,4-TDA) has been compared in two commercially available RHS to normal human skin ex vivo, and in primary epidermal keratinocytes and dermal fibroblasts as well as in vitro generated epidermal Langerhans cells and dermal dendritic cells. The mono N-acetylated derivative N-(3-amino-4-methyl-phenyl)acetamide (M1) was the only metabolite detectable in substantial amounts indicating the predominance of N-acetylation. RHS exceeded human skin ex vivo in N-acetyltransferase activity and in cell cultures metabolite formation ranked as follows: keratinocytes > fibroblasts ~ Langerhans cells ~ dendritic cells. In conclusion, our results underline the principal suitability of RHS as an adequate test matrix for the investigation of N-acetylation of xenobiotics which is most relevant for risk assessment associated with cutaneous exposure to aromatic amines.
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany.
Lisa
L
Grohmann
Institute of Pharmacy (Pharmaceutical and Medicinal Chemistry), Freie Universität Berlin, Berlin, Germany.
Daniel
D
Becker
Institute of Pharmacy (Pharmaceutical and Medicinal Chemistry), Freie Universität Berlin, Berlin, Germany.
Jörg
J
Rademann
Institute of Biomaterial Science (Biocompatibility), Helmholtz Zentrum Geesthacht, Teltow, Germany.
Nan
N
Ma
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany.
Monika
M
Schäfer-Korting
Institute of Pharmacy (Pharmacology and Toxicology), Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195, Berlin, Germany. Guenther.Weindl@fu-berlin.de.
Günther
http://orcid.org/0000-0002-4493-7597
G
Weindl
D000107:Acetylation; D001711:Biotransformation; D002478:Cells, Cultured / Q000187:drug effects; D062109:Dermatologic Surgical Procedures; D004817:Epidermis / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008658:Inactivation, Metabolic; D015603:Keratinocytes; D010655:Phenylenediamines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D019651:Plastic Surgery Procedures; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000493:pharmacokinetics
D010655:Phenylenediamines; D015262:Xenobiotics; C010914:2,4-diaminotoluene
2,4-Toluenediamine; Extrahepatic metabolism; N-Acetyltransferase; Reconstructed human skin