Temporal variations in drug metabolism and cellular stress modulated by environmental factors as determinants of idiosyncratic liver toxicity
Idiosyncratic drug reactions (IDRs) are a rare but major complication of drug therapy and drug development. Although a basic understanding of the chemical and biological events leading to idiosyncratic drug toxicity is still lacking, it appears that an individual´s susceptibility to rare adverse drug reactions is determined by the interaction of metabolic, genetic and environmental factors. Thus, genetic or environmental factors that increase reactive metabolite formation, alter cellular stress and immune response, or a combination of these may be critical determinants in the response to an otherwise non-toxic drug. The objectives of this project are to explore the relationship between reactive metabolite formation and molecular signaling after continuous exposure to a model drug associated with drug idiosyncrasy and to test the hypothesis that various environmental factors may reduce the threshold for liver toxicity through modulation of drug metabolism and/or sensitization of the liver through up-regulation of co-stimulatory factors. It is expected that results from these studies will not only provide a better understanding of the basic mechanisms related to idiosyncratic drug reactions, but will also help establish animal models more relevant to the human situation with improved sensitivity to predict potential drug hazards. Moreover, results from these studies may contribute to a more fundamental understanding as to how environmental factors or co-exposure to chemicals may introduce temporal variability into the susceptibility of an individual by altering the threshold of toxicity of a compound.