Regulation of hepatobiliary transporters during cholestasis may mediate the phenomenon of adaptation to cholestasis induced by rifampicin in rats

Background: It is known that antituberculosis drugs initially induce liver injury, and then the liver progressively adapts to the drug and mitigates the drug-induced liver injury. This study aimed to explore the molecular mechanisms responsible for liver adaptation to Rifampicin (RFP). Methods: RFP was administered at a dose of 100 mg/kg.d to rats for 7 weeks. On days 0, 7, 14, 21, 28, 35, 42, and 49, 0.5 ml of blood was drawn for use in liver biochemistry assays. Liver tissues were collected on days 7, 14, and 49 for examination of the expression of multidrug resistance protein 2 (Mrp2), bile salt export pump (Bsep), multidrug resistance protein 4 (Mrp4), and sodium-dependent taurocholate cotransporting polypeptide (Ntcp) by quantitative RT-PCR and Western blotting. Results: The serum alkaline phosphatase, total bilirubin, and direct bilirubin levels and liver TBA level began to rise at day 7, reached peak levels in week 1 or 2, and then declined gradually over time in RFP-treated rats. MRP4 mRNA expression was significantly increased on day 49. The expression of Ntcp protein was significantly decreased on day 49. The expression of Mrp4 and Bsep protein increased, reaching peak levels on days 14 and 49, respectively. Conclusions: Liver adaptation to RFP for mitigation of liver injury is likely mediated through the regulation of hepatobiliary transporters.