Nrf2- and PPARα-Mediated Regulation of Hepatic Mrp Transporters after Exposure to Perfluorooctanoic Acid and Perfluorodecanoic Acid

• DOI: 10.1093/toxsci/kfn177
• Publication Date: 2008-08-30T00:46:24Z
• Authors: Jonathan M. Maher; Lauren M. Aleksunes; Matthew Z. Dieter; Yuji Tanaka; Jeffrey M. Peters; Jose E. Manautou; Curtis D. Klaassen
• Keywords: Perfluorooctanoic acid

Perfluorooctanoic acid and perfluorodecanoic (PFDA) are commonly used as emulsifiers surfactants in fluoropolymer manufacturing known peroxisome proliferator–activated receptor alpha (PPARα) agonists. PPARα activation induces β- ω-oxidation enzymes such Cyp4a14 acyl-CoA oxidase, which a likely cause of subsequent oxidative stress proliferation. Conversely, NF-E2-related factor-2 (Nrf2) is transcription factor that protects against inflammation by regulating several detoxification xenobiotic transporter genes. Because PFDA markedly hepatic metabolism stress, we hypothesized exposure would increase expression efflux multidrug resistance–associated protein (Mrp) transporters. A single dose (80 mg/kg) administered to mice increased Mrp3 (fourfold) Mrp4 (31-fold) mRNA expression. Upregulation correlated with elevated serum-conjugated bilirubin bile acids, respectively. To determine the mechanism induction, was Nrf2-null mice, PPARα-null pretreated gadolinium chloride, Kupffer cell–depleting chemical capable inhibiting inflammatory cytokine response. In both PPARα- maximal induction after administration attenuated. Gadolinium chloride pretreatment reduced serum tumor necrosis factor-α levels treatment, well 30%, suggesting cell–derived mediators may contribute Mrp induction. Thus, administration, liver mounts compensatory hepatoprotective response via Nrf2, increasing expression, corresponding increases substrates.