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ToxSci Advance Access published online on February 16, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp030
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Reactivity Profiling: Covalent Modification of Single Nucleophile Peptides for Skin Sensitisation Risk Assessment

Maja Aleksic, Emma Thain, Delphine Roger, Ouarda Saib, Michael Davies, Jin Li, Aynur Aptula and Raniero Zazzeroni

Safety and Environmental Assurance Centre, Unilever, Colworth Science Park, Sharnbrook, Bedford MK44 1LQ, UK

Corresponding author: Maja Aleksic. Safety and Environmental Assurance Centre, Unilever Colworth, Sharnbrook, Bedford MK44 1LQ, UK; Tel. +44 1234 264 993. Fax. +44 1234 264 744. E-mail: maja.aleksic{at}unilever.com

Received December 22, 2008; revision received February 6, 2009; accepted February 7, 2009


  Abstract

The molecular basis of chemical allergy is rooted in the ability of an allergen (hapten) to modify endogenous proteins. This mechanistic understanding aided development of screening assays which generate reproducible quantitative and qualitative reactivity data. Such assays use model peptides with a limited number and type of protein nucleophiles and the data does not reflect the specificity, variety and complexity of hapten interactions with multiple nucleophiles. Building on these developments we extended the standardised approach to maximise the type and the amount of information that can be derived from an in chemico assay. We used a panel of six single nucleophile peptides and individually optimised the incubation conditions to favour chemical modification. Employing LC-MS/MS technique we simultaneously obtained multiple quantitative and qualitative measurements (% peptide depletion, adduct(s) formation, and peptide dimerisation for Cys containing peptide). Using these methods we obtained reactivity data for 36 chemicals of known skin sensitising potency. By optimising incubation conditions we ensured detection of all reactive chemicals. We explored the LC-MS/MS approach to generate kinetic data for 10 chemicals allowing further characterisation of reactivity and a potentially more robust quantitative reactivity descriptor. Our ultimate aim is to integrate this dataset with available physicochemical data and outputs from other predictive assays, all addressing different key steps in the induction of sensitisation, to help us make decisions about the safe use of chemicals without using animal tests. The epidermal protein target sites, modification of which may be immunogenic and lead to induction of skin sensitisation are currently unknown. Increasing the understanding of this process may help further refine in chemico reactivity assays as well as aid the interpretation of the reactivity data.

Key Words: skin sensitisation; covalent binding; model peptide; mass spectrometry; in chemico; hapten.


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