Application of Metabonomics in Predictive Toxicology

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DESCRIPTION (provided by applicant): The major long-term objectives of the research in this proposal are to identify factors that improve the predictability of reactive metabolite-mediated drug-induced liver injury (DILI) and to characterize biochemical pathways that are differentially affected by intrinsic vs. idiosyncratic hepatotoxins. To address these objectives, three drugs that are known to cause DILI in humans, and their regioisomers and/or close structural analogues that cause significantly different toxicological responses, will be investigated in mice or rats by comparing transcriptomic and metabonomic profiles of the drugs and their isomers/analogues. Specifically, we will compare transcriptomic and metabonomic/metabolomic profiles 1) of the acetanilide analgesic/anfipyretic drug, acetaminophen, an intrinsic hepatotoxicant, to its less toxic regioisomer, 3'-hydroxyacetanilide, 2) of the thiophene-containing drug, tienilic acid, an immune-mediated toxicant, to a regioisomer that causes intrinsic hepatocellular injury, and 3) of the nitroaromafic anti-androgen drug, flutamide, an idiosyncratic hepatotoxicant, to its less toxic cyano analogue. The use of isomers and close structural analogues will allow for a more refined search for potential biomarkers of DILI since their similar physicochemical characterisfics and pharmacological responses should help differenfiate toxicological effects from therapeutic and off-target pharmacological effects. This paradigm also should aid in characterization of mechanisms and pathways involved in their toxicity. Whereas dysregulation of genes will be assessed by microarray hybridization analysis of RNA from animal livers, metabolic changes will be assessed by high field nuclear magnefic resonance and liquid chromatography-mass spectrometry of animal serum samples collected through time. A combination of analysis of variance and chemometric approaches will be used to integrate the information obtained from the transcriptomics and metabonomics/ metabolomics studies. The goal is to understand changes in genetic and metabolic pathways over time that are affected by drugs that cause liver injury. Adverse drug reacfions cause significant morbidity and mortality, and many drugs have either been removed from the market or have "Black Box" warnings because of DILI. Results of the proposed research should help in the selection of safer drug candidates for development by the pharmaceutical industry, and also should provide insights into why some individuals are more susceptible to DILI than others. Ultimately, biomarkers may be measured in readily accessible human fluids (e.g., blood and urine) that can be used to identify those individuals who are most at risk if they take certain drugs.