Fig. 1. Combination of gefitinib and APAP induced hepatotoxicity in mice and cell death in hepatocytes. (A) Schematic diagram gefitinib and APAP co-administration. ICR mice were treated with 75 mg/kg gefitinib daily, with additional 100 mg/kg APAP given on three days a week by intragastric administration continuously for 5 weeks (n=6), and liver tissues were harvested after the mice were sacrificed. (B) Serum samples were collected to analyze the levels of ALT and AST (n=6). (C) Relative liver weights were calculated (n=6). (D) Liver sections were stained with H&E for histopathological analysis. Yellow arrowheads indicated the cellular level showing karyopyknosis with an eosinophilic cytoplasm that were suggestive of cell death in specific regions. For 400× magnification, scale bar: 50 μm. (E) Cell proliferation inhibition was examined by the SRB assays. HL-7702 cells were exposed to different concentrations of gefitinib and/or APAP for 48 h. Survival rates were calculated and shown as mean ± SEM from three independent experiments (n=3). (F) HL-7702 cells were exposed to indicated dose of gefitinib (10 μM) and/or APAP (1.25 mM) for 24 h. Cells were photographed by microscopy. The data are expressed as the mean ± SEM; *p<0.05; **p<0.01; ***p<0.001. ALT, alanine aminotransferase; APAP, acetaminophen; AST, aspartate aminotransferase; BW, body weight; GEFI, gefitinib; LW, liver weight; H&E, hematoxylin and eosin; SRB, sulforhodamine B.
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