The Nrf2-Keap1-ARE Toxicity Pathway as a Cellular Sensor for Skin Sensitizers—Functional Relevance and a Hypothesis on Innate Reactions to Skin Sensitizers

With the tight deadlines set both by the public and by the regulatory authorities to replace animal tests for toxicological endpoints relevant to the development of cosmetic products, a large number of research projects have recently focused on cellular endpoints affected by skin sensitizing compounds. The general aim stated in these projects was to find "markers" for skin sensitizers, be it at the level of the transcriptome or at the protein level. Rather than talking of "cellular markers," the new paradigm "Toxicity testing in the 21st century" formulated by the National Academy of Sciences in the United States focuses on "Toxicity pathways." A specific marker for any given toxicological endpoint can only exist, if specific toxicity pathways, comprising specific sensors, are linked to this endpoint. In the context of skin sensitization, one has to ask whether there is an innate cellular signaling pathway activated by skin sensitizers. Here a significant body of evidence, mainly accumulated in the last 20 months, is reviewed, indicating that indeed the Nrf2-Keap1-ARE regulatory pathway is such a toxicity pathway activated by cysteine-reactive skin sensitizers. Whereas first indications on the in vivo relevance are available, key questions remain open and can now specifically be addressed. A minority of sensitizers, more specifically reacting with lysine residues, appears not to activate the Nrf2-Keap1-ARE pathway and might trigger yet another unknown toxicity pathway.