PMID- 22023385
OWN - NLM
STAT- MEDLINE
DCOM- 20120402
LR  - 20131121
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 24
IP  - 11
DP  - 2011 Nov 21
TI  - Relating skin sensitizing potency to chemical reactivity: reactive Michael 
      acceptors inhibit NF-kappaB signaling and are less sensitizing than S(N)Ar- and 
      S(N)2- reactive chemicals.
PG  - 2018-27
LID - 10.1021/tx2003678 [doi]
AB  - 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-kappaB 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.
FAU - Natsch, Andreas
AU  - Natsch A
AD  - Givaudan Schweiz AG, Duebendorf, Switzerland. andreas.natsch@givaudan.com
FAU - Haupt, Tina
AU  - Haupt T
FAU - Laue, Heike
AU  - Laue H
LA  - eng
PT  - Journal Article
DEP - 20111107
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Lactones)
RN  - 0 (NF-kappa B)
RN  - 0 (Peptides)
RN  - 0 (Plant Extracts)
RN  - 0 (Sesquiterpenes)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - Z4ZG7O5SZ9 (Picryl Chloride)
SB  - IM
MH  - Animals
MH  - Arnica/*chemistry
MH  - Dermatitis, Allergic Contact/immunology/*metabolism
MH  - Humans
MH  - I-kappa B Kinase/immunology/metabolism
MH  - Immunization
MH  - Kinetics
MH  - Lactones/chemistry/immunology/*metabolism
MH  - Local Lymph Node Assay
MH  - Mice
MH  - NF-kappa B/immunology/metabolism
MH  - Peptides/chemistry/*metabolism
MH  - Picryl Chloride/chemistry/immunology/*metabolism
MH  - Plant Extracts/chemistry
MH  - Quantitative Structure-Activity Relationship
MH  - Sesquiterpenes/chemistry/immunology/*metabolism
MH  - Signal Transduction/immunology
MH  - Skin/immunology/*metabolism
EDAT- 2011/10/26 06:00
MHDA- 2012/04/03 06:00
CRDT- 2011/10/26 06:00
PHST- 2011/10/26 06:00 [entrez]
PHST- 2011/10/26 06:00 [pubmed]
PHST- 2012/04/03 06:00 [medline]
AID - 10.1021/tx2003678 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2011 Nov 21;24(11):2018-27. doi: 10.1021/tx2003678. Epub 2011 
      Nov 7.