Assessing concordance of drug-induced transcriptional response in rodent liver and cultured hepatocytes

Gene expression studies in model systems are widely used for understanding the mechanism of drugs and other perturbations in biological systems. Other researchers have examined the reproducibility of microarray studies between laboratories, or comparing microarrays and/or RNA sequencing. However, no large scale studies have compared results from protocols which differ in minor details, or results generated in vivo vs. in vitro culture system thought to serve as useful models. The rat liver is by far the most extensively studied model evaluating effects of drugs and other perturbations, and existing data allowed us to assess the level of concordance between rat liver and rat primary hepatocytes cultured in collagen-coated plates (i.e. “flat” culture) for hundreds of drugs. We found that the mouse liver serves as a better model of the rat liver than do rat primary hepatocytes, even after allowing for differences due to pharmacokinetics. The low concordance observed between rat liver and rat hepatocytes suggests that validating the utility of ‘omics data generated on emerging cell culture approaches (e.g. “organ-on-a-chip”, 3D-printed tissues) using rat cells and comparison to the rat liver may be necessary in order to gain confidence these approaches substantially improve on traditional culture models of human cells.