PT - JOURNAL ARTICLE AU - Jacqueline Bezencon AU - James J Beaudoin AU - Katsuaki Ito AU - Dong Fu AU - Sharin E Roth AU - William J Brock AU - Kim LR Brouwer TI - Altered Expression and Function of Hepatic Transporters in a Rodent Model of Polycystic Kidney Disease AID - 10.1124/dmd.119.086785 DP - 2019 Jan 01 TA - Drug Metabolism and Disposition PG - dmd.119.086785 4099 - http://dmd.aspetjournals.org/content/early/2019/06/03/dmd.119.086785.short 4100 - http://dmd.aspetjournals.org/content/early/2019/06/03/dmd.119.086785.full AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common form of inherited polycystic kidney disease (PKD) and is a leading cause of kidney failure. Patients with ADPKD develop fluid-filled cysts in their kidneys, and often form cysts in their liver and other organs. Previous data have shown that bile acids are increased in the liver of polycystic kidney (PCK) rats, a rodent model of ADPKD; these changes may be associated with alterations in liver transporter expression and function. However, the impact of PKD on hepatic transporters has not been characterized. Therefore, this preclinical study was designed to investigate hepatic transporter expression and function in PCK compared to wild-type (WT) Sprague Dawley rats. Transporter gene expression was measured by qPCR, and protein expression was quantified by western blot and LC-MS/MS-based proteomic analysis in rat livers. Transporter function was assessed in isolated perfused livers (IPLs), and biliary and hepatic total glutathione content were measured. Protein expression of Mrp2 and Oatp1a4 was decreased 3-fold and 2.9-fold, respectively, in PCK rat livers based on western blot analysis. Proteomic analysis confirmed a decrease in Mrp2 and a decrease in Oatp1a1 expression (PCK/WT ratios of 0.368[plusmn]0.098 and 0.563[plusmn]0.038, respectively; mean[plusmn]SD). The biliary excretion of 5(6)-carboxy-2',7'-dichlorofluorescein (CDF), a substrate of Oatp1a1, Mrp2, and Mrp3, was decreased 28-fold in PCK compared to WT rat IPLs. Total glutathione was significantly reduced in the bile of PCK rats. Differences in hepatic transporter expression and function may contribute to altered disposition of Mrp2 and Oatp substrates in PKD.SIGNIFICANCE STATEMENT N/A