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ToxSci Advance Access published online on October 11, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm259
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Skin sensitizers induce antioxidant response element dependent genes: Application to the in vitro testing of the sensitization potential of chemicals

A. Natsch*,{dagger} and R. Emter*

* Givaudan Schweiz AG, Ueberlandstrasse 138, CH-8600 Duebendorf, Switzerland

{dagger} corresponding author, andreas.natsch{at}givaudan.com, Tel.: ++41 44 824 21 05, Fax: ++41 44 824 29 26

Received August 31, 2007; revision received October 2, 2007; accepted October 2, 2007


  Abstract

Tests for skin sensitization are required prior to the market launch of new cosmetic ingredients and in vitro tests are needed to replace the current animal tests. Protein reactivity is the common feature of skin sensitizers and it is a crucial question whether a cellular in vitro assay can detect protein reactivity of diverse test chemicals. The signaling pathway involving the repressor protein Keap1 and the transcription factor Nrf2, which binds to the antioxidant response element (ARE) in the promoter of many phase II detoxification genes, is a potential cellular marker since Keap1 had been shown to be covalently modified by electrophiles which leads to activation of ARE-dependent genes. To evaluate whether this regulatory pathway can be used to develop a predictive cellular in vitro test for sensitization, 96 different chemicals of known skin sensitization potential were added to Hepa1C1C7 cells and the induction of the ARE regulated quinone reductase (QR) activity was determined. In parallel 102 chemicals were tested on the reporter cell line AREc32, which contains an 8-fold repeat of the ARE sequence upstream of a luciferase gene. Among the strong/extreme skin sensitizers 14 out of 15 and 30 out of 34 moderate sensitizers induced the ARE-dependent luciferase activity and in many cases this response was paralleled by an induction of QR activity in Hepa1C1C7 cells. 60% of the weak sensitizers also induced luciferase activity, and the overall accuracy of the assay was 82.2%. Only 5 out of 32 tested non-sensitizers induced low levels of luciferase activity, indicating a high specificity of the assay. Thus, measurement of the induction of this signaling pathway provides an interesting in vitro test to screen for the skin sensitization potential of novel chemicals.

Key Words: Skin sensitization; in vitro testing; antioxidant response element.


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