From xenobiotic chemistry and metabolism to better prediction and risk assessment of skin allergy.

摘要

Allergic contact dermatitis (ACD) is a condition that can have a serious impact on quality of life. The manifestation of ACD is dependent upon the primary sensitisation of an individual to a specific substance following skin exposure. It is important to identify and manage the risks associated with exposure to known skin sensitisers, in both the manufacture and use of consumer products. At present, the only validated approaches to conclusively identify sensitisation hazard and estimate potency are in vivo models such as the local lymph node assay. No in vitro test methods exist for this endpoint. There is an urgent need to develop novel in vitro/in silico testing or risk assessment strategies to replace animal testing. It is envisaged that such novel approaches can only be developed on the foundation of a good mechanistic understanding of skin sensitisation. Early stages of sensitisation are thought to be dependent upon the extent of compound absorption and bioavailability, rates of metabolic activation or detoxification and intrinsic reactivity of the bioavailable xenobiotic electrophile with skin protein nucleophiles. This review explores general chemical and metabolic aspects in relation to the potential formation of protein-hapten conjugates. Despite the complexities and poor understanding of some of the metabolic processes involved in skin sensitisation, it is possible to describe some of the relationships between chemical structures and the ability to form covalent conjugates with proteins. A prototypical group of xenobiotics that have been used to explore sensitisation mechanisms in some detail are selected cinnamic derivatives: a discussion of recent work using these compounds is presented as a case study. Novel aspects for future research in this area are also discussed.