Role of ABCB1 and ABCB4 in renal and biliary excretion of perfluorooctanoic acid in mice

Abstract

Background: Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown. Methods: In this study, two ABC transporters, ABCB1 and ABCB4, were examined in mice with single intravenous PFOA administration (3.13 μmol/kg). To identify candidate renal PFOA transporters, we used a microarray approach to evaluate changes in gene expression of various kidney transporters in 𝘈𝘣𝘤𝘣𝟦 null mice. Results: Biliary PFOA concentrations were lower in 𝘈𝘣𝘤𝘣𝟦 null mice (mean « standard deviation: 0.25 « 0.12 μg/mL) than in wildtype mice (0.87 « 0.02 μg/mL). Immunohistochemically, ABCB4 expression was confirmed at the apical region of hepatocytes. However, renal clearance of PFOA was higher in 𝘈𝘣𝘤𝘣𝟦 null mice than in wild-type mice. Among 642 solute carrier and ABC transporters, 5 transporters showed significant differences in expression between wild-type and 𝘈𝘣𝘤𝘣𝟦 null mice. These candidates included two major xenobiotic transporters, multidrug resistance 1 (𝘈𝘣𝘤𝘣𝟣) and organic anion transporter 3 (𝘚𝘭𝘤𝟤𝟤𝘢𝟪). 𝘈𝘣𝘤𝘣𝟣 mRNA levels were higher in 𝘈𝘣𝘤𝘣𝟦 null mice than in wild-type mice in kidney. In 𝘈𝘣𝘤𝘣𝟦 null mice, 𝘈𝘣𝘤𝘣𝟣𝘣 expression was enhanced in proximal tubules immunohistochemically, while that of 𝘚𝘭𝘤𝟤𝟤𝘢𝟪 was not. Finally, in 𝘈𝘣𝘤𝘣𝟣𝘢/𝘣 null mice, there was a significant decrease in the renal clearance of PFOA (0.69 « 0.21 vs 1.1mL « 0.37/72 h in wild-type mice). A homology search of ABCB1 showed that several amino acids are mutated in humans compared with those in rodents and monkeys. Conclusions: These findings suggest that, in the mouse, 𝘈𝘣𝘤𝘣𝟦 and 𝘈𝘣𝘤𝘣𝟣 are excretory transporters of PFOA into bile and urine, respectively.