Advances in molecular toxicology-towards understanding idiosyncratic drug toxicity

Idiosyncratic drug toxicity is a major complication of drug therapy and drug development. Such adverse drug reactions (ADRs) include anaphylaxis, blood dyscrasias, hepatotoxicity and severe cutaneous reactions. They are usually serious and can be fatal. At present, prediction of idiosyncratic ADRs at the preclinical stage of drug development is not possible because there are no suitable animal models and we do not understand the basic mechanisms involved in the toxicity when it does occur in man. Many idiosyncratic reactions appear to have an immunological aetiology. For example, there is increasing evidence for the role of T lymphocytes in severe skin reactions. Nevertheless, the sequence of events by which a simple chemical can elicit severe tissue damage remains poorly understood and alternative novel mechanisms of toxicity must also be explored. The purpose of this article will be to review the currently accepted mechanisms of idiosyncratic drug toxicity at the chemical and the molecular levels. In particular, we will consider how recent advances in cellular immunology and molecular biology can improve our understanding of both the chemical and clinical aspects of drug hypersensitivity. Recent advances in the role of both inter- and intra-cellular signalling in the regulation of the immune response to drugs and their metabolites will be discussed. The long-term aim of such research is to provide test systems for the evaluation of drug safety and patient susceptibility to idiosyncratic drug toxicity.