Understanding how small molecules comprising just a few dozen or less atoms inflict permanent harm upon complex living cells – which contain thousands upon thousands of metabolites, genes, proteins and interconnected signalling networks – is a central concern in modern toxicology. While toxicologists were long restricted to observational descriptions of morphological changes in dying cells, modern developments in chemistry and molecular biology opened the door to new mechanistic understandings of toxicity. One useful concept emerging from this effort proposes noxious xenobiotics bind selectively to ‘toxicity receptors’ in much the same way medicinal agents target ‘drug receptors’ to elicit a pharmacological response. An even more influential insight recognises that instead of inducing toxicity via transient interactions with receptor proteins, many toxic xenobiotics instead undergo enzyme-catalysed conversion to electrophilic metabolites that react chemically with cell macromolecules. This chapter explores the basic properties of reactive metabolites that influence their toxicological properties together with the major deleterious consequences of reactive metabolite formation within tissues, including adduct formation, calcium dyshomeostasis, oxidative stress, lipid peroxidation, apoptosis and kinase activation.
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