Our current understanding of the toxicological implications of chemically reactive metabolites has its origins in the pioneering work of the Millers in the late 1940s, who demonstrated that a number of carcinogenic azo dyes and related polycyclic aromatics underwent bioactivation to electrophilic intermediates that became covalently bound to nucleic acids and proteins. The link between metabolic activation and toxicity was further developed in the 1970s by Brodie, Gillette, Mitchell and co-workers to explain the organ damage caused by a variety of therapeutic agents, which led to the introduction of screening paradigms in the pharmaceutical industry designed to reduce the formation of reactive metabolites from candidate drugs. Even though the precise relationship between bioactivation and toxicity remains poorly understood, recent findings have underscored the importance of the 'body burden' of reactive metabolites as one determinant of toxicity. This presentation will summarize contemporary views on the role of reactive metabolites in drug-induced toxicity, and highlight future directions of research in this field.

Chemically reactive metabolites: Past, present, and future

244th National Meeting (2012)

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