Pfoa-Mediated Regulation Of Bcrp Transporter Expression And Function

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.