Relating skin sensitizing potency to chemical reactivity: reactive Michael acceptors inhibit NF-κB signaling and are less sensitizing than S(N)Ar- and S(N)2- reactive chemicals.
The skin sensitization potency of chemicals is partly related to their reactivity to proteins. This can be quantified as the rate constant of the reaction with a model peptide, and a kinetic profiling approach to determine rate constants was previously proposed. A linear relationship between the skin sensitization potency in the local lymph node assay (LLNA) and the rate constant for Michael acceptors was reported, characterized by a relatively flat regression line. Thus, a 10-fold increase of reactivity correlates to an increase of the sensitization potential of only 1.7-fold. Here, we first validate this model by repeating previous data and testing additional Michael acceptors and prove that the model is both reproducible and robust to the addition of new data. Chemicals of different mechanistic applicability domains, namely, S(N)Ar- and S(N)2-reactive sensitizers, were then tested with the same kinetic profiling approach. A linear relationship between sensitization potency in the LLNA and rate constants was also found, yet with a much steeper slope, i.e., for S(N)Ar- and S(N)2-reactive sensitizers, increasing reactivity correlates to a much stronger increase in sensitization potency. On the basis of the well-known inhibitory activity of some Michael acceptors on IKK kinase, it was hypothesized that the difference in the slopes is due to the specific anti-inflammatory potential of Michael acceptor chemicals. Therefore, all chemicals were tested for anti-inflammatory activity in a reporter gene assay for the inhibition of NF-κB activation. Increasingly reactive Michael acceptors have increasing anti-inflammatory potential in this assay, whereas no such biological activity was detected for the S(N)Ar and S(N)2 reactive sensitizers. Thus, the increasing reactivity of Michael acceptors confers both anti-inflammatory and skin sensitizing/pro-inflammatory potential, which may partially neutralize each other. This may be the reason for the relatively weak relationship between the potency in the LLNA and the rate constant of this particular group of chemicals.
Givaudan Schweiz AG, Duebendorf, Switzerland. andreas.natsch@givaudan.com
Andreas
A
Natsch
Tina
T
Haupt
Heike
H
Laue
D000818:Animals; D018650:Arnica / Q000737:chemistry*; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000276:immunology / Q000378:metabolism; D007114:Immunization; D007700:Kinetics; D007783:Lactones / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D023441:Local Lymph Node Assay; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D010853:Picryl Chloride / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D012717:Sesquiterpenes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000276:immunology / Q000378:metabolism*
D007783:Lactones; D016328:NF-kappa B; D010455:Peptides; D010936:Plant Extracts; D012717:Sesquiterpenes; D051550:I-kappa B Kinase; D010853:Picryl Chloride