Dysregulation of BSEP and MRP2 May Play an Important Role in Isoniazid-Induced Liver Injury via the SIRT1/FXR Pathway in Rats and HepG2 Cells

To explore the role of the abnormal expression of the bile salt export pump (BSEP) and multidrug resistance protein 2 (MRP2) in isoniazid (INH)-induced liver injury, we assessed the liver injury induced by INH in rats and HepG2 cells in vitro. The regulatory pathways via Sirtuin 1 (SIRT1) and farnesoid X receptor (FXR) were also determined. Rat liver injury was assessed by histopathological and biochemical analysis and HepG2 cytotoxicity was assessed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. The levels of protein were determined by Western blot. The results indicated that INH could induce hepatotoxicity in vivo and in vitro in a dose dependent manner. The liver index and serum biochemical analysis, especially the levels of total bile acids (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL), were significantly increased in rats. The INH hepatotoxicity was severe in the high dose group, and occurred alongside the down-regulation of BSEP and MRP2 in vivo and in vitro, leading to the accumulation of toxic substrates in the hepatocytes. The SIRT1/FXR pathway was identified as being important for the down-regulation of transporters. In summary, our study indicated that the down-regulation of BSEP and MRP2 represents one mechanism of INH-induced liver injury and the down-regulation of SIRT1/FXR may be a key regulator. This will inform the development of novel therapies and enable the prevention of INH-induced liver injury.