Metabolic modeling of sex-specific tissue predicts mechanisms of differences in toxicological responses.

Male-bias in clinical testing of drugs has led to a disproportionate number of hepatotoxic events in women. Previous works use gene-by-gene differences in biological sex to explain this discrepancy, but there is little focus on the systematic interactions of these differences. To this end, we use a combination of gene expression data and metabolic modeling to compare metabolic activity between the male and female liver and treated and untreated hepatocytes. We find several subsystems with differential activity in each sex; however, when comparing these subsystems with those pathways altered by hepatotoxic agents, we find little overlap. To explore these differences on a reaction-by-reaction basis, we use the same sex-specific transcriptomic data to contextualize the previously published Human1 human cell metabolic model. In these models we find a difference in flux for the import of bile acids and salts, suggesting a potential difference in enterohepatic circulation. These findings can help guide future drug design, toxicological testing, and sex-specific research to better account for the entire human population.