Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, United States; Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT, 06340, United States.
Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research & Development, Pfizer Inc., Groton, CT, 06340, United States.
Chemosphere. 2024 Aug;361:142390. doi: 10.1016/j.chemosphere.2024.142390. Epub 2024 May 25.
Per- and polyfluoroalkyl substances (PFAS) encompass a diverse group of synthetic fluorinated chemicals known to elicit adverse health effects in animals and humans. However, only a few studies investigated the mechanisms underlying clearance of PFAS. Herein, the relevance of human renal transporters and permeability to clearance and bioaccumulation for 14 PFAS containing three to eleven perfluorinated carbon atoms (η = 3-11) and several functional head-groups was investigated. Apparent permeabilities and interactions with human transporters were measured using in vitro cell-based assays, including the MDCK-LE cell line, and HEK293 stable transfected cell lines expressing organic anion transporter (OAT) 1-4 and organic cation transporter (OCT) 2. The results generated align with the Extended Clearance Classification System (ECCS), affirming that permeability, molecular weight, and ionization serve as robust predictors of clearance and renal transporter engagement. Notably, PFAS with low permeability (ECCS 3A and 3B) exhibited substantial substrate activity for OAT1 and OAT3, indicative of active renal secretion. Furthermore, we highlight the potential contribution of OAT4-mediated reabsorption to the renal clearance of PFAS with short η, such as perfluorohexane sulfonate (PFHxS). Our data advance our mechanistic understanding of renal clearance of PFAS in humans, provide useful input parameters for toxicokinetic models, and have broad implications for toxicological evaluation and regulatory considerations.
全氟和多氟烷基物质 (PFAS) 是一组多样化的合成含氟化学品，已知会对动物和人类产生不良健康影响。然而，只有少数研究调查了 PFAS 清除的机制。在此，研究了人类肾脏转运体和通透性对清除和生物累积的相关性，研究了含有 3 到 11 个全氟碳原子 (η=3-11) 和几个功能头基的 14 种 PFAS。使用体外基于细胞的测定法，包括 MDCK-LE 细胞系和表达有机阴离子转运体 (OAT) 1-4 和有机阳离子转运体 (OCT) 2 的 HEK293 稳定转染细胞系，测量了表观渗透率和与人类转运体的相互作用。生成的结果与扩展清除分类系统 (ECCS) 一致，证实了通透性、分子量和电离度是清除和肾脏转运体参与的可靠预测因子。值得注意的是，通透性低的 PFAS (ECCS 3A 和 3B) 对 OAT1 和 OAT3 表现出显著的底物活性，表明其具有主动的肾脏分泌作用。此外，我们强调了 OAT4 介导的重吸收对 PFAS（如全氟己烷磺酸盐 (PFHxS)）短 η 的肾脏清除的潜在贡献。我们的数据增进了我们对人类肾脏清除 PFAS 的机制理解，为毒代动力学模型提供了有用的输入参数，并对毒理学评价和监管考虑具有广泛的意义。
