Downregulation of hepatic sulfotransferase 1E1 expression associated with decreased expression of multidrug resistance-associated protein 2

Changes in the expression of drug-metabolizing Enzymes and transporters can alter the pharmacokinetics of drugs, potentially affecting their efficacy and safety. In this study, we investigated the effects of decreased multidrug resistance-associated protein (MRP) 2 expression on the gene expression of Other drug-metabolizing Enzymes and transporters. Variations in the mRNA expression of drug-metabolizing Enzymes and transporters were observed in MRP2-knockdown human hepatocellular carcinoma HepG2 cells and the liver of MRP2-deficient Eisai hyperbilirubinemic rats (EHBR). Both models showed decreased mRNA and protein expression of sulfotransferase (SULT) 1E1, a phase II drug-metabolizing enzyme, suggesting a relationship between the transcriptional regulation of MRP2 and SULT1E1. The plasma levels of bilirubin, bile acids, and Cholesterol were higher in EHBR than in control Sprague-Dawley rats. Treatment with chenodeoxycholic acid (CDCA), a primary bile acid, reduced SULT1E1 mRNA expression in HepG2 cells and suppressed human SULT1E1 promoter activity in a luciferase reporter assay using HepG2 cells. CDCA is a known agonist of the farnesoid X receptor (FXR), and transcriptome analysis of the EHBR liver also suggested FXR activation, as inferred from changes in its target gene expression. These findings suggest that decreased MRP2 expression causes coordinated changes in the SULT1E1 gene expression via FXR activation by endogenous substances. These indirect changes in the expression of drug-metabolizing Enzymes or transporters should be considered during drug development and in clinical practice. SIGNIFICANCE STATEMENT: This study investigated compensatory or coordinated changes in gene expression of drug-metabolizing Enzymes and transporters in multidrug resistance-associated protein (MRP) 2-knockdown HepG2 cells and in the liver of MRP2-deficient rats. Decreased expression of MRP2 affects the gene expression of drug-metabolizing Enzymes and transporters, including a decrease in SULT1E1, likely through nuclear receptor activation by endogenous molecules.

Drug transporters; Drug-metabolizing enzymes; Eisai hyperbilirubinemic rats; Multidrug resistance–associated protein 2; Sulfotransferase 1E1; Transcriptional regulation.