The molecular mechanism underlying the induction of hepatic MRP3 expression and function by omeprazole

This study aimed to assess changes in fold‐induction of MRP3 mRNA and protein expression over controls in omeprazole‐treated HepG2 cells after transient transfection of human MRP3 siRNA, or after pretreatment of actinomycin D (Act‐D). Furthermore, MRP3 siRNA knock‐down or MRP‐specific inhibition (indomethacin) was used to determine whether induced MRP3 protein by omeprazole could possess enhanced efflux transport. The results demonstrated that omeprazole induced MRP3 mRNA and protein expression in a concentration‐ and time‐dependent manner. Moreover, that induction was almost completely abolished by addition of human MRP3 siRNA and also by pretreatment of Act‐D, respectively. In addition, the decay rate of MRP3 mRNA in vehicle‐ and omeprazole‐treated cells was similar in the presence of Act‐D, suggesting transcriptional up‐regulation of MRP3 mRNA expression by omeprazole. Most importantly, omeprazole induced MRP3 efflux transport activity as measured by 5‐carboxyfluorescein assay in the presence or absence of human MRP3 siRNA or indomethacin. We conclude that omeprazole can induce MRP3 mRNA and protein expression and enhance MRP3 efflux transport activity through the transcriptional up‐regulation, and that omeprazole can also induce other MRP transporters. This article is protected by copyright. All rights reserved.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research