HepG2 and primary mouse hepatocytes
Figure 5.6: Cholestasis network in HepG2 cells and primary mouse hepatocytes after exposure to acetaminophen (APAP), cyclosporin A (CsA) and amiodarone (Amio) across time. Cholestasis was a GeneGO Liver toxicity endpoint process that was significantly altered in HepG2 cells and primary mouse hepatocytes after treatment with acetaminophen, amiodarone and cyclosporin A. The red and blue thermometers denote up-regulation and downregulation, respectively. The thermometer numbering corresponds to HepG2: (1) APAP_24h, (2) APAP_48h, (3) APAP_72h, (4) CsA_24h, (5) CsA_48h and (6) CsA_72h, (7) Amio_24h, (8) Amio_48h, (9) Amio_72h of exposure; and to primary mouse hepatocytes: (A) APAP_24h, (B) APAP_48h, (C) CsA_24h, (D) CsA_48h, (E) Amio_24h and (F) Amio_48h of exposure. The green and red lines between elements denote stimulation and inhibition, respectively. The gray arrows denote unknown interaction between the elements. Significantly up-regulated or down-regulated genes: FC ≥ 1.5 (p-value < 0.05) or FC ≤ -1.5 (p-value < 0.05), respectively. The boxes on the lines denote the type of regulation: M= microRNA binding; TR=transcriptional regulation; +P = phosphorylation; B = binding; CS = complex subunit; GR = group relation.
ToxProfiler was used to further identify possibly conserved responses between the HepG2 cells and primary mouse hepatocytes. Acetaminophen induced in both cell types biochemical pathways related to major liver functions. These are glycolysis/gluconeogenesis, primary bile acid biosynthesis (down-regulated in agreement with the changes related with cholestasis at pathway (MetaCore™) and gene level), glycine, serine and threonine metabolism, chromosome, transporters, complement and coagulation cascades and PPAR signaling pathway. These conserved acetaminophen-induced pathways are all down-regulated, except for chromosome-related pathways, Previously, it was also shown that acetaminophen modulates biochemical pathways and processes related to major liver functions such as fatty acid me-
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