Figure 6. Comparative analyses of rat and human biomarker predictions and species-specific trends across perturbations.

(a) Heatmap of 16 metabolite biomarkers predicted to increase (purple) or decrease (orange) in response to 16 individual compounds. Metabolite production scores for rat (upper left triangle) and human (lower right triangle) hepatocytes were generated by integrating treatment-induced gene expression changes into iRno and iHsa using TIMBR. Rat and human production scores across all 286 metabolites were classified as positively correlated (FDR<0.1), uncorrelated or negatively correlated (FDR<0.1) for each individual compound. Compounds were ordered by correlation coefficients and metabolites were ordered by average production scores across all 76 compounds.BHB, β-hydroxybutryate; PGE2, prostaglandin E2. (b) Scatterplot comparing rat and human production scores for PGE2 across 76 compounds. Two antipyretic compounds with known cyclooxygenase inhibitor activities, acetaminophen and ibuprofen, were predicted to consistently decrease prostaglandin E2 production in both rat and human hepatocytes. (c) Scatterplot comparing rat and human production scores for urate across 76 compounds. Rat production scores for urate were consistently decreased by anti-gout medications that are known to reduce urate accumulation (colchicine, phenylbutazone, benziodarone and benzbromarone). Human production scores were also decreased for anti-gout compounds with the exception of benzbromarone. (d) Rat production scores in response to two xanthine derivatives, caffeine and theophylline, were strongly correlated. Biomarker predictions associated with glutamate, urate, glucose and urea were individually consistent across both compounds. (e) Human production scores in response to theophylline and caffeine were less correlated than rat production scores. Glutamate and urate were predicted to increase in response to theophylline and decrease in response to caffeine for human hepatocytes, whereas glucose and urea predictions were consistent across both compounds. Compared with rat production scores (d), urate, glucose and glutamate would be considered species-specific predictions. (f) Chemical structures for theophylline and caffeine differ by a single methyl group. Rat biomarker predictions did not indicate any potential differences between the two xanthine derivatives.In patients, theophylline is known to cause increased serum levels of urate⁶⁵.