Molecular mechanisms of adverse drug reactions

Background: Other than alkylating agents used in cancer chemotherapy, most drugs that cause adverse reactions require metabolism to structures that can react with constituents of our cellular environment to form products that initiate a chain of chemical and biochemical events leading to cellular damage. The mechanisms of formation of reactive metabolites that can cause cellular injury, the nature of the enzymes involved in their formation, and the structures of reactive intermediates have been characterized in some cases. Much less is known about the mechanisms of interaction of reactive metabolites with cellular molecules and how that interaction leads to tissue injury. Objective: This paper focuses on the general mechanisms involved in the formation of reactive metabolites and the drug structures commonly associated with these reactions. Methods: Both MEDLINE and TOXLINE databases were searched through the year 2000, and additional books and articles published through March 2001 were reviewed. Mechanisms for the formation of reactive metabolites from the following general substructures are described: arylacetic and arylpropionic acid nonsteroidal anti-inflammatory drugs, anilines and anilides, hydrazines and hydrazides, aromatic and heteroaromatic compounds, halogenated alkyl compounds, and fatty acid-like compounds. A few specific drugs (eg, acetaminophen, felbamate, troglitazone) and herbal products (eg, pennyroyal) are used as examples to illustrate the likely role of the metabolism of specific substructures in drug-mediated toxicities. Conclusions: Substantial toxicologic experience with some chemical substructures and research on reactive metabolite formation from these structures have provided a basis for semiempirical assessment of possible risk from these structures. The adult and pediatric populations are subject qualitatively to similar risks, but quantitatively the degree of risk may vary, depending on several factors.