An integrative approach to identify biomarkers and investigate mechanisms of adverse drug reactions - Project Summary/Abstract Idiosyncratic adverse drug reactions (IADRs) occur in a small but significant percentage of the population, are unpredictable, and frequently cause life-threatening events requiring intensive medical care. IADRs are typically only discovered late in drug development, or after a drug is approved and widely available. Most IADRs are presumed to be immune mediated. Genetic predisposition has been identified as a risk factor in some IADRs with specific human leukocyte antigen (HLA) alleles associated with specific IADRs. A single drug can cause strikingly different IADR phenotypes and be linked with different HLA markers based on phenotype. Drug metabolism has also been an important focus of IADR etiology. Reactivity of drug metabolites as measured by the formation of protein adducts correlates with the tendency of a drug to cause an IADR. Reactive metabolites have been implicated in forming haptens and activating antigen-presenting cells, yet few studies investigate the interface between drug metabolites and immune-mediated reactions. We plan to leverage our prior work to build an integrative research platform that addresses multiple factors involved in the development of IADRs. We will focus our research on trimethoprim-sulfamethoxazole (TMP-SMX) IADRs given our group’s extensive experience with this drug. TMP-SMX is a commonly used antibiotic and is associated with unpredictable, life- threatening IADRs including severe skin, liver, and lung injury. Our goal is to combine metabolism, genetics and immune signaling studies to identify putative biomarkers for TMP-SMX IADRs. Our approach includes identifying tissue specific metabolites to evaluate how these molecules interact with immune pathways and antigen presentation. We plan to 1) identify high risk metabolites based upon abundance, reactivity and tissue specificity, 2) use the identified metabolites to probe immune pathway responses, 3) determine the influence of selected metabolites on HLA peptide presentation. Through the integration of drug metabolism, immune signaling, and HLA antigen presentation, we will gain a greater understanding of IADR biomarkers and mechanistic insight. Our overall vision of this research program is that our multi-pronged approach will enhance IADR research resulting in the safer use of drugs.
