DuPont Haskell Global Centers for Health and Environmental Sciences, Newark, Delaware 19714, United States.
Chem Res Toxicol. 2012 Jan 13;25(1):35-46. doi: 10.1021/tx200363w. Epub 2011 Oct 25.
Sex-, species-, and chain length-dependent renal elimination is the hallmark of mammalian elimination of perfluorocarboxylates (PFCAs) and has been extensively studied for almost 30 years. In this review, toxicokinetic data of PFCAs (chain lengths ranging from 4 to 10) in different species are compared with an emphasis on their relevance to renal elimination. PFCAs vary in their affinities to bind to serum albumins in plasma, which is an important factor in determining the renal clearance of PFCAs. PFCA-albumin binding has been well characterized and is summarized in this review. The mechanism of the sex-, species-, and chain length-dependent renal PFCA elimination is a research area that has gained continuous interest since the beginning of toxicological studies of PFCAs. It is now recognized that organic anion transport proteins play a key role in PFCA renal tubular reabsorption, a process that is sex-, species-, and chain length-dependent. Recent studies on the identification of PFCA renal transport proteins and characterization of their transport kinetics have greatly improved our understanding of the PFCA renal transport mechanism at the molecular level. A mathematical representation of this renal tubular reabsorption mechanism has been incorporated in physiologically based pharmacokinetic (PBPK) modeling of perfluorooctanoate (PFOA). Improvement of PBPK models in the future will require more accurate and quantitative characterization of renal transport pathways of PFCAs. To that end, a basolateral membrane efflux pathway for the reabsorption of PFCAs in the kidney is discussed in this review, which could provide a future research direction toward a better understanding of the mechanisms of PFCA renal elimination.
性、种属和链长依赖性肾脏排泄是哺乳动物消除全氟羧酸（PFCAs）的标志，已经被广泛研究了近 30 年。在这篇综述中，比较了不同物种中 PFCAs（链长从 4 到 10）的毒代动力学数据，重点是它们与肾脏排泄的相关性。PFCAs 在与血浆中血清白蛋白结合的亲和力上存在差异，这是决定 PFCAs 肾清除率的一个重要因素。PFCAs-白蛋白结合已得到很好的描述，并在本综述中进行了总结。性、种属和链长依赖性肾脏 PFCAs 消除的机制是自 PFCAs 毒理学研究开始以来一直受到持续关注的研究领域。现在人们认识到，有机阴离子转运蛋白在 PFCAs 的肾小管重吸收中发挥关键作用，这一过程具有性、种属和链长依赖性。最近关于鉴定 PFCAs 肾脏转运蛋白及其转运动力学特征的研究极大地提高了我们对 PFCAs 肾脏转运机制的分子水平的理解。这种肾小管重吸收机制的数学表示已被纳入全氟辛烷磺酸（PFOA）的生理相关药代动力学（PBPK）模型中。未来 PBPK 模型的改进将需要更准确和定量地描述 PFCAs 的肾脏转运途径。为此，本文讨论了肾脏中 PFCAs 重吸收的基底外侧膜外排途径，这可能为更好地理解 PFCAs 肾脏消除机制提供一个未来的研究方向。
