Serious adverse drug reactions remain an ever present concern for all clinicians who utilize therapeutic drugs in children and adults. The term """"""""idiosyncratic"""""""" drug toxicity refers to relatively rare, but potentially life-threatening events in which the factors predisposing to the event are largely unknown, but are thought to be unique to the individual. These forms of toxicity are frequently devastating, both physically and emotionally, to patients and their families, and also present a burden to society through delayed diagnoses, prolonged hospital- izations with dramatic consumption of healthcare resources, litigation and inappropriate generalizations regarding risk that often restrict the use of therapeutic entities that could be safely given to most patients. Using hypersensitivity reactions to the aromatic anticonvulsant carbamazepine as a model system, the long-term objective of this proposal is to characterize the critical events that may determine individual susceptibility to idiosyncratic drug toxicity. It is hypothesized that the individual's own immune system is responsible for the tissue injury observed clinically, and that bioactivation of carbamazepine to reactive metabolites capable of irreversibly binding to cellular proteins is a necessary event leading to the immune response. Furthermore, the drug metabolizing enzyme generating the reactive metabolite, a cytochrome P450, is itself a target of the reactive metabolite. To identify the link between the drug bioactivation event and the subsequent immune response, this proposal will test the hypothesis that covalently modified P450s are degraded within the cell by pathways similar to those used for antigen processing and presentation to the immune system. Furthermore, this hypothesis implies that the particular amino acid sequences recognized by patient antibodies mimic similar peptides of infectious origin. Thus, environmental (infection), drug metabolism (P450 and detoxification enzyme genotype or phenotype) and immune (HLA haplotype) factors may all determine susceptibility to idiosyncratic events. The ultimate goal is to use all the relevant bioactivation, detoxification and immune response factors to construct a """"""""susceptibility profile"""""""" that can be used to identify a priori individuals at risk using specific genotyping and phenotyping methods. Thus, these basic science techniques can be used to effectively address a clinical problem affecting patients of all ages, pediatric to geriatric. It is anticipated that the basic experimental paradigm employed for these studies can also be applied to other idiosyncratic toxicities with suspected drug bioactivation and immune etiologies.
