Investigation of the hepatotoxicity of flutamide: pro-survival/apoptotic and necrotic switch in primary rat hepatocytes characterized by metabolic and transcriptomic profiles in microfluidic liver biochips.

摘要: We investigated the effects of liver damage induced by flutamide in primary rat hepatocytes using microfluidic biochips. Flutamide is a non-steroidal anti-androgenic drug. Two concentrations, 10 μM and 100 μM, were used to expose for 24h under perfusion. Thanks maintenance hepatocyte differentiation phenotype biotransformation performance cultures, metabolic ratio analysis hydroxyflutamide, flutamide-gluthatione hydroxyflutamide-gluthatione productions demonstrated saturation drug's process high level at when compared μM. A microarray comparing (10 or μM) with controls revealed common response both concentrations illustrated modulating expression mRNA genes associated mitochondrial perturbation, proliferator-activated receptors (Ppar) signaling, lipid fatty acid metabolism, antioxidant defense, cell death pathways, consistently vitro vivo reports. Additionally literature reports, our integration transcriptomic profiles specific dose dependent response. found typical pro-survival/apoptosis network activation (through IGF/PDGFD upstream route via downstream up regulation CREB5, BCL2, IKBKG routes PI3K/signaling). also down levels sugar amino metabolism pathways. At necrosis switch was observed tight junctions' pathway, cellular aggregation reduction viability. Altogether data potential sensitivity cultures evaluate xenobiotic toxicity improving reproducing results. Finally, we proposed two integrated synthetic networks describe exposure flutamide.