Idiosyncratic toxicity: the role of toxicophores and bioactivation

Drugs and chemicals can undergo enzyme-catalyzed bioactivation reactions within cellular systems, with the formation of reactive chemical species. These reactive metabolites can lead to thiol depletion, reversible protein modification (glutathionylation and nitration), further irreversible protein adduct formation and subsequent irreversible protein damage. The incorporation of potentially reactive chemical moieties - toxicophores - within new therapeutic agents should be limited. However, this cannot always be prevented, particularly when the structural feature responsible for toxicity is also responsible for the pharmacological efficacy. The identification and further knowledge of critical levels of thiol depletion and/or covalent modification of protein will aid in the development of new drugs. Importantly, the identification of drug-thiol conjugation should provide a warning of potential problems, yet not hinder the development of a potentially therapeutically useful drug.