<p class="first" id="d1463520e183">Bile acid transporters and the nuclear factor erythroid
2-related factor (Nrf-2)-mediated
adaptive response play important roles in the development of drug-induced liver injury
(DILI). However, little is known about the contribution of the adaptive response to
rifampicin (RFP)-induced cell injury. In this study, we found RFP decreased the survival
rate of HepG2 cells and increased the levels of lactate dehydrogenase (LDH), alanine
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP),
γ-glutamyl-transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), indirect
bilirubin (IBIL), total bile acid (TBA) and adenosine triphosphate (ATP) in the cell
culture supernatants in both a concentration- and a time-dependent manner. RFP increased
the expression levels of bile acid transporter proteins and mRNAs, such as bile salt
export pump (BSEP), multidrug resistance protein 1 (MDR1), multidrug resistance-associated
protein 2 (MRP2), Na+/taurocholate cotransporter (NTCP), organic anion transporting
protein 2 (OATP2), organic solute transporter β (OSTβ) and Nrf2. Following the transient
knockdown of Nrf2 and treatment with RFP, the expression levels of the BSEP, MDR1,
MRP2, NTCP, OATP2 and OSTβ proteins and mRNAs were decreased to different degrees.
Moreover, the cell survival was decreased, whereas the LDH level in the cell culture
supernatant was increased. Overexpression of the Nrf2 gene produced the opposite effects.
Treatment with tauroursodeoxycholic acid (TUDCA) increased the expression levels of
the bile acid transporters and Nrf2, decreased the expression levels of glucose-regulated
protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4),
and C/EBP-homologous protein (CHOP), and inhibited RFP-induced oxidative stress. Moreover,
TUDCA reduced cell apoptosis, increased cell survival and decreased the levels of
LDH, ALT, AST, AKP, γ-GT, TBIL, DBIL, IBIL, TBA and ATP in the cell culture supernatant.
Therefore, TUDCA alleviates RFP-induced injury in HepG2 cells by enhancing bile acid
transporters expression and the Nrf2-mediated adaptive response.
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