SBIR Phase I Research: This proposal aims to examine the predictive utility of an in vivo primate toxicogenomic model of human hepatotoxicity. Hepatotoxicity is the most significant and common adverse drug reaction. A central challenge to pharmaceutical drug development therefore is the early identification and elimination of drug candidates with unfavorable liver toxicity profiles. The ability to employ microarrays to measure global gene expression patterns that precede biochemical and pathologic change has contributed to the emergence of toxicogenomics as a promising method of rapidly assessing potential toxicity. As with conventional toxicity assays, however, interspecies biological differences may pose a significant limitation to predictive toxicogenomics. Due to genomic and physiologic similarities, toxicogenomic studies in nonhuman primates may improve the relevance to human toxicity and associated molecular mechanisms. The proposed studies test the hypotheses that transcriptional changes can be detected in primate hepatic tissue in vivo that are predictive of primate hepatotoxicity, and hence human hepatotoxicity, and that these transcriptional changes are reflective of the severity of conventional biochemical and pathological toxicity measures in a dose dependant manner. Changes in gene expression in liver tissue, liver pathology and serum ALT, LDH, bilirubin, prothrombin time and glucose will be assessed at multiple time points following acute administration of acetaminophen, a widely used analgesic with intrinsic hepatotoxicity. This will allow a determination of the sequence of transcriptional changes that parallel or proceed histologic and biochemical events. Transcriptional changes induced by an established hepatotoxic dose of acetaminophen will be evaluated, as well as changes induced by two lower doses, the lower of which is estimated not to be hepatotoxic. The resulting dose response data will allow the identification of transcriptional profiles that are associated with acetaminophen toxicity and distinguishable from other biological effects. Defining the chronologic and dose dependent gene expression changes induced by acetaminophen may reveal a unique early transcriptional profile that is predictive of hepatic injury from this widely used medication, providing support for the utility of primate based toxicogenomics. Sharing of tissue, blood, and urine samples and data with FDA and NIEHS collaborators will allow comparisons with their parallel rodent data and add complementary data on accessible biomarkers and metabonomics.
