The breast cancer resistance protein (Bcrp) is an efflux transporter that participates in the biliary and renal excretion of drugs and environmental chemicals. Recent evidence suggests that pharmacological activation of the peroxisome proliferator activated receptor alpha (PPARα) can up-regulate the hepatic expression of Bcrp. The current study investigated the regulation of hepatic and renal Bcrp mRNA and protein in mice treated with the PPARα agonist perfluorooctanoic acid (PFOA) and the ability of PFOA to alter human BCRP function in vitro. Bcrp mRNA and protein expression were quantified in the livers and kidneys of male C57BL/6 mice treated with vehicle or PFOA (1 or 3 mg/kg/day oral gavage) for 7 days. PFOA treatment increased liver weights as well as the hepatic mRNA and protein expression of the PPARα target gene, cytochrome P450 4a14. Compared to vehicle-treated control mice, PFOA increased hepatic Bcrp mRNA and protein between 1.5- and 3-fold. Immunofluorescent staining confirmed enhanced canalicular Bcrp staining in liver sections from PFOA-treated mice. The kidney expression of cytochrome P450 4a14 mRNA, but not Bcrp, was increased in mice treated with PFOA. Micromolar concentrations of PFOA decreased human BCRP ATPase activity and inhibited BCRP-mediated transport in inverted membrane vesicles. Together, these studies demonstrate that PFOA induces hepatic Bcrp expression in mice and may inhibit human BCRP transporter function at concentrations that exceed levels observed in humans.
Pregnancy increases the urinary excretion of chemicals in women and rodents. It is unknown whether the enhanced clearance of drugs during pregnancy involves changes in the expression of transporters that mediate chemical secretion and reabsorption. The purpose of this study was to quantify the mRNA and protein expression of efflux transporters in kidneys from virgin and pregnant mice on gestational days 7, 11, 14, and 17 and postnatal days 1, 15, and 30 with use of quantitative polymerase chain reaction, Western blot, and immunofluorescence. Multidrug resistance protein (Mdr) 1b mRNA, multidrug resistance-associated protein (Mrp) 4 mRNA, and protein levels decreased significantly by 25-75% throughout pregnancy and lactation. Similarly, Mrp2 and multidrug and toxin extrusion transporter (Mate) 1 mRNA expression were down-regulated 20-40% during mid to late gestation but returned to control levels by postnatal day 15. In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine. IntroductionPregnancy-induced hormonal and hemodynamic changes significantly alter renal function. In humans and rodents, increases in cardiac output and renal vasodilation enlarge the size of the kidneys, elevate renal plasma flow by 50-85%, and increase the rate of glomerular filtration by 40-65% (Chapman et al., 1998;Conrad, 2004;Maynard and Thadhani, 2009;Cornelis et al., 2011). Clinically, pregnant women exhibit proteinuria, glucosuria, and aminoaciduria, which have been attributed to alterations in renal function (Davison and Dunlop, 1980;Cornelis et al., 2011). Together, hyperfiltration and increased blood flow to the kidneys alter maternal pharmacokinetics by elevating the renal clearance of chemicals during pregnancy.Renal transporters are membrane-spanning proteins that play a critical role in facilitating the movement of toxins and drugs into the urine via secretion and into the blood via reabsorption. To enable these processes, transporters are prominently localized on both the apical (brush border) and basolateral membranes of proximal tubule epithelial cells. Transporters expressed within the kidneys are members of one of the two superfamilies: the solute carrier (SLC) and ATP-binding cassette (ABC) families. Efflux transporters that extrude chemicals from cells are members of both the ABC and the SLC families and include the multidrug resistance-associated proteins (Mrps), multidrug resistance proteins (Mdrs), breast cancer resistance protein (Bcrp), and multidrug and toxin extrusion proteins (Mates) (reviewed in Klaassen and Aleksunes, 2010).Recent studies have begun to explore transporter regulation in the kidneys during pregnancy and the subsequent postpartum period. In one study, expression of renal Mdr1b mRNA in mice decreased between mid and late gestation, with little to no change at the protein level (...
Renal xenobiotic transporters are important determinants of urinary secretion and reabsorption of chemicals. In addition to glomerular filtration, these processes are key to the overall renal clearance of a diverse array of drugs and toxins. Alterations in kidney transporter levels and function can influence the efficacy and toxicity of chemicals. Studies in experimental animals have revealed distinct patterns of renal transporter expression in response to sex hormones, pregnancy, and growth hormone. Likewise, a number of disease states including diabetes, obesity, and cholestasis alter the expression of kidney transporters. The goal of this review is to provide an overview of the major xenobiotic transporters expressed in the kidneys and an understanding of metabolic conditions and hormonal factors that regulate their expression and function.
Prior research suggests that sex hormones and metabolic changes, such as obesity and hyperglycemia, can alter renal transporter expression in rodents. The purpose of this study was to characterize the expression of kidney efflux transporters and regulatory transcription factors in response to Type I diabetes and pregnancy. Female C57BL/6 mice were treated with multiple low doses of streptozotocin (STZ) to induce hyperglycemia and then mated with normoglycemic male mice. Transporter mRNA and protein expression were quantified in kidneys from vehicle- and STZ-treated non-pregnant and pregnant mice on gestation day 14. Pregnancy decreased the expression of Mdr1b, Mrp4, and 5 proteins and increased the mRNA and protein expression of Mrp3 by 50 to 60%. STZ treatment elevated Mrp1, 2, 4, and 5 and reduced Mrp3, 6, and Mdr1b mRNA and/or protein in non-pregnant mice. Pregnancy had little effect on STZ-mediated changes in renal efflux transporter expression. Transcriptional profiles of Hnf1α, PXR, AhR, and Nrf2 were altered in patterns similar to some efflux transporters suggesting potential involvement in their regulation. Taken together, these results suggest that renal drug efflux transporters and regulatory signaling pathways are altered by endocrine and metabolic changes that occur during pregnancy and Type I diabetes.
Due to prior industrial use and lack of biodegradability, perfluorooctanoic acid (PFOA) has accumulated in human serum, which may have negative health effects. However, transporter‐mediated excretion of PFOA has not yet been elucidated. The purpose of this study was to determine if interactions exist between PFOA and the breast cancer resistance protein (BCRP/ABCG2), an efflux transporter found in hepatocytes and renal proximal tubule cells. ATPase assay and membrane vesicle experiments were used to assess PFOA interactions with BCRP. Protein and mRNA were measured in kidneys and livers of male C57BL/6 mice treated with PFOA (1 or 3 mg/kg/d po for 7 days). In the ATPase assay, PFOA decreased transporter activity in sulfasalazine‐activated BCRP membranes. PFOA inhibited BCRP‐mediated transport in membrane vesicles between 47 and 69% at high concentrations (25 and 50 μM). As expected, PFOA treatment increased liver weights and hepatic and renal Cyp4a14 mRNA and protein in mice. Likewise, Bcrp mRNA and protein increased in livers by 136% and 128% from baseline, respectively. In kidneys, Bcrp protein levels were elevated 50% and a trend for increased mRNA was observed. In conclusion, PFOA induces Bcrp protein and mRNA transcript levels in mice and may inhibit Bcrp transporter function at high concentrations; whether inhibition is competitive or allosteric was not evident.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.