Insights into the Competitive Mechanisms of Per- andPolyfluoroalkyl Substances Partition in Liver and Blood
Insights into the Competitive Mechanisms of Per- andPolyfluoroalkyl Substances Partition in Liver and Blood
复制标题
深入了解全氟烷基和多氟烷基物质在肝脏和血液中分配的竞争机制
DOI：
10.1021/acs.est.1c08493
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发表时间：
2022-05-17
影响因子：
11.4
通讯作者：
Zhu, Lingyan
中科院分区：
文献类型：
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作者：
Jia, Yibo;Zhu, Yumin;Zhu, Lingyan
一些全氟烷基和多氟烷基物质（PFASs）容易在肝脏中蓄积并引起肝毒性。然而，直接测量人体肝脏中PFAS浓度的困难阻碍了我们对其肝毒性和作用机制的理解。我们研究了11种PFAS在雄性CD-1小鼠肝脏和血液中的分配。尽管全氟烷磺酸（PFSAs）在小鼠血清中的蓄积量高于相应的羧酸（PFCAs），但PFSAs的肝-血分配系数（RL/S）低于PFCAs的RL/S，表明肝脏和血液之间存在竞争。体外实验进一步表明，人肝脂肪酸结合蛋白（hL-FABP）与血清白蛋白（HSA）的竞争结合是决定分配的主要因素。测定PFAS与两种蛋白质的结合亲和力（Kd）。RL/Sand logKd（hL？）FABP）/logKd（HSA）比logKd（hL？结果表明，hL-FABP与HSA的竞争结合是分配的主要控制因素。因此，可以从现有的血清浓度预测所选PFAS在人体中的肝脏浓度，这对于评估其肝毒性是重要的。
Some per- and polyfluoroalkyl substances (PFASs) tend to beaccumulated in liver and cause hepatotoxicity. However, the difficulty to directlymeasure liver concentrations of PFASs in humans hampers our understanding oftheir hepatotoxicity and mechanisms of action. We investigated the partitioning of11 PFASs between liver and blood in male CD-1 mice. Although accumulation ofthe perfluoroalkanesulfonic acids (PFSAs) in mice serum was higher than theircarboxylic acids (PFCAs) counterparts as expected, the liver-blood partitioncoefficients (RL/S) of PFSAs were lower than the PFCAsRL/S, implying acompetition between liver and blood. Thein vitroexperiments further indicatedthat the partitioning was dominantly determined by their competitive bindingbetween human liver fatty acid binding protein (hL-FABP) and serum albumin(HSA). The binding affinities (Kd) of PFASs to both proteins were measured. Thecorrelations between theRL/Sand logKd (hL???FABP)/logKd (HSA)were stronger than those with logKd (hL???FABP)alone, magnifying thatthe partitioning was dominantly controlled by competitive binding between hL-FABP and HSA. Therefore, the liver concentrationsof the selected PFASs in humans could be predicted from the available serum concentrations, which is important for assessing theirhepatotoxicity.