Influence of Formulation Change and Cyp2c19 Genotypes On Pharmacokinetics of Single-Dose Rabeprazole In Healthy Chinese Adults By Lc-Ms/Ms

Abstract

e72 Volume 37 Number 8S cancer-associated or drug-induced liver injury. In this study we investigated to what extent FXR is regulated by miR-192-3p. Material and Methods: Two putative binding sites for miR-192-3p within the FXR-3’UTR were predicted in silico and tested in vitro by performing Luciferase reporter assays. The NR1H4-3’UTR was subcloned into pmirGlo reporter vector in wild-type and mutated form and co-transfected into Huh-7 cells together with miR-192-3p. To study the endogenous miR-192-3p-dependent expression of FXR and FXRregulated target genes Huh-7 cells were treated for 48 hours and 72 hours with miRNA mimic or negative control. MRNA and protein expression were measured using TaqMan technology and western blot analysis. FXR and miR-192 expression levels obtained in colon cancer tissue samples from 65 patients were correlated using Pearson’s correlation analysis. Results: MiR-192-3p binds specifically to the FXR-3’UTR and significantly decreases luciferase activity. Transfection of Huh-7 cells with miR-192-3p led to a significant decrease in FXR mRNA and protein levels as well as mRNA levels of the FXR-inducible bile acid transporters OSTα -OSTβ and OATP1B3. Significant inverse correlations of miR-192 and FXR expression were observed in colon cancer-derived samples. Conclusions: MiR-192-3p negatively regulates the expression of FXR, thereby significantly decreasing the expression of the FXR-inducible target genes OSTα /β and OATP1B3. Because of the role of miR-192 in cancerogenesis, this miRNA-dependent mechanism of FXR regulation could affect the expression of FXR target genes in liver and colon cancer.