Matrix Effect
of Human Reconstructed Epidermis on
the Chemoselectivity of a Skin Sensitizing α‑Methylene-γ-Butyrolactone:
Consequences for the Development of <i>in Chemico</i> Alternative
Methods
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Abstract
Adoption
of new legislations and social pressure are pushing toward
the development of alternative methods to the use of animals for the
assessment of most toxicological end-points including skin sensitization.
To that respect, much efforts have been put in the first step of the
adverse outcome pathway focusing on chemical interactions taking place
between sensitizing chemicals or haptens and epidermal proteins. However,
these <i>in chemico</i> approaches have been so far only
based on the use of model nucleophiles, amino acids, peptides, or
proteins in water/buffer solution and focused mainly on thiol reactivity.
These studies even if bringing a valuable set of information are very
far from reflecting chemical interactions that may happen between
a xenobiotic and nucleophiles present in a complex heterogeneous tissue
such as the epidermis. Recently, we have shown that using a high-resolution
magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) technique
it was possible to characterize chemical interactions taking place
between a skin sensitizer and nucleophilic amino acids present in
a 3-D reconstructed human epidermis (RHE). We have now compared the
chemical reactivity and chemoselectivity of a sensitizing α-methylene-γ-butyrolactone
toward human serum albumin used as a model protein and RHE. Using
this technique, we showed that amino acid modifications by this hapten
was different according to the model used and that in RHE histidine
residues seem to have an important role in the formation of adducts.
Obviously, the role of histidine in the induction of skin sensitization
has been so far neglected and should probably be taken into account
for the refinement of <i>in chemico</i> approaches for the
detection and potency classification of skin sensitizers