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首页> 外文期刊>Toxicological sciences: An official journal of the Society of Toxicology >Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid.
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Nrf2- and PPAR alpha-mediated regulation of hepatic Mrp transporters after exposure to perfluorooctanoic acid and perfluorodecanoic acid.

机译：暴露于全氟辛酸和全氟癸酸后，Nrf2-和PPARα介导的肝脏Mrp转运蛋白的调节。

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Perfluorooctanoic acid and perfluorodecanoic acid (PFDA) are commonly used as emulsifiers and surfactants in fluoropolymer manufacturing and are known peroxisome proliferator-activated receptor alpha (PPAR alpha) agonists. PPAR alpha activation induces beta- and omega-oxidation enzymes such as Cyp4a14 and acyl-CoA oxidase, which are a likely cause of subsequent oxidative stress and peroxisome proliferation. Conversely, NF-E2-related factor-2 (Nrf2) is a transcription factor that protects against oxidative stress and inflammation by regulating several detoxification and xenobiotic transporter genes. Because PFDA markedly induces hepatic metabolism and oxidative stress, we hypothesized that PFDA exposure would increase expression of hepatic efflux multidrug resistance-associated protein (Mrp) transporters. A single PFDA dose (80 mg/kg) administered to mice increased hepatic Mrp3 (fourfold) and Mrp4 (31-fold) mRNA expression. Upregulation of Mrp3 and Mrp4 correlated with elevated serum-conjugated bilirubin and bile acids, respectively. To determine the mechanism of Mrp3 and Mrp4 induction, PFDA was administered to Nrf2-null mice, PPAR alpha-null mice, and mice pretreated with gadolinium chloride, a Kupffer cell-depleting chemical capable of inhibiting the inflammatory cytokine response. In both PPAR alpha- and Nrf2-null mice, maximal induction of Mrp3 and Mrp4 mRNA after PFDA administration was attenuated. Gadolinium chloride pretreatment reduced serum and hepatic tumor necrosis factor-alpha levels after PFDA treatment, as well as Mrp4 mRNA expression by 30%, suggesting that Kupffer cell-derived mediators may contribute to Mrp induction. Thus, after PFDA administration, the liver mounts a compensatory hepatoprotective response via PPAR alpha and Nrf2, markedly increasing Mrp3 and Mrp4 expression, with corresponding increases in serum of known Mrp3 and Mrp4 substrates.
机译：全氟辛酸和全氟癸酸（PFDA）在氟聚合物制造中通常用作乳化剂和表面活性剂，并且是已知的过氧化物酶体增殖物激活受体α（PPARα）激动剂。 PPARα激活诱导β-和ω-氧化酶，例如Cyp4a14和酰基-CoA氧化酶，这可能是随后的氧化应激和过氧化物酶体增殖的可能原因。相反，NF-E2相关因子2（Nrf2）是一种转录因子，可通过调节几种排毒和异源转运蛋白基因来保护其免受氧化应激和炎症。因为PFDA显着诱导肝代谢和氧化应激，所以我们假设PFDA暴露会增加肝外排多药耐药相关蛋白（Mrp）转运蛋白的表达。给予小鼠单次PFDA剂量（80 mg / kg）可增加肝Mrp3（四倍）和Mrp4（31倍）mRNA表达。 Mrp3和Mrp4的上调分别与血清结合胆红素和胆汁酸升高有关。为了确定Mrp3和Mrp4诱导的机制，对Nrf2无效的小鼠，PPARα无效的小鼠以及用氯化g（一种能够抑制炎症细胞因子反应的枯否细胞消灭剂）预处理的小鼠施用PFDA。在PPAR alpha和Nrf2无效的小鼠中，PFDA给药后对Mrp3和Mrp4 mRNA的最大诱导作用减弱。氯化预处理可降低PFDA治疗后的血清和肝肿瘤坏死因子-α水平，并使Mrp4 mRNA表达降低30％，这表明库普弗细胞衍生的介质可能有助于Mrp的诱导。因此，在施用PFDA之后，肝脏会通过PPARα和Nrf2进行代偿性肝保护反应，从而显着增加Mrp3和Mrp4的表达，并相应增加已知Mrp3和Mrp4底物的血清。

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