Are chemically reactive metabolites responsible for adverse reactions to drugs?

Low molecular weight organic chemicals can be transformed by normal drug-metabolising systems into short-lived metabolites that are inherently reactive towards cellular macromolecules. There is direct evidence that the formation of such chemically reactive metabolites may lead to mutagenesis, carcinogenicity, apoptosis and necrosis in both cell and animal models. A number of drugs associated with non-pharmacological drug toxicities in man have been shown to undergo bioactivation either in vivo or in vitro. We have therefore examined the evidence for the role of reactive metabolites in the three most common drug-induced toxicities: hepatotoxicity, skin reactions and blood dyscrasias.