Organophosphate triesters and selected metabolites enhance binding of thyroxine to human transthyretin in vitro
Organophosphate triesters and selected metabolites enhance binding of thyroxine to human transthyretin in vitro
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DOI：
10.1016/j.toxlet.2017.12.030
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发表时间：
2018-03-15
影响因子：
3.5
通讯作者：
Letcher, Robert J.
中科院分区：
文献类型：
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作者：
Hill, Katie L.;Hamers, Timo;Letcher, Robert J.
用作阻燃剂和增塑剂的有机磷酸酯 (OP) 三酯的毒理学特性目前尚不清楚，但越来越多的证据表明它们会影响甲状腺系统。甲状腺激素（TH）转运的扰动是可能影响甲状腺功能的一种作用机制。本研究应用甲状腺素 (T4) 和人转甲状腺素蛋白 (hTTR) 转运蛋白的体外竞争性蛋白结合测定来确定 OP 三酯、TDCIPP（磷酸三（1,3-二氯-2-丙基））、TBOEP（磷酸三（丁氧基乙基））、TEP（磷酸三乙酯）、TPHP（磷酸三苯酯）、p-OHTPHP（对羟基三苯磷酸酯）和OP 二酯 DPHP（磷酸二苯酯），以竞争性地取代 hTTR 中的 T4。对于六种 OP 酯，观察到 T4 与 hTTR 的结合增强，而不是假设的竞争，并且呈浓度依赖性。例如，T4-hTTR 结合在 TBOEP 浓度低至 64 nM 时显着增加，在 5000 nM 时高达对照的 184%。据我们所知，对这些结果的合理解释可能是 OP 酯与 hTTR 的变构相互作用，允许 T4 进入 TH 结合袋的第二个位点。这些体外结果表明，OP 酯毒性的新机制是通过 T4 结合增强，以及 T4-hTTR 相互作用的可能失调。
The toxicological properties of organophosphate (OP) triesters that are used as flame retardants and plasticizers are currently not well understood, though increasing evidence suggests they can affect the thyroid system. Perturbation of thyroid hormone (TH) transport is one mechanism of action that may affect thyroid function. The present study applied an in vitro competitive protein binding assay with thyroxine (T4) and human transthyretin (hTTR) transport protein to determine the potential for the OP triesters, TDCIPP (tris(1,3-dichloro-2-propyl) phosphate), TBOEP (tris(butoxyethyl) phosphate), TEP (triethyl phosphate), TPHP (triphenyl phosphate), p-OHTPHP (para-hydroxy triphenyl phosphate), and the OP diester DPHP (diphenyl phosphate), to competitively displace T4 from hTTR. Enhancement of T4 binding to hTTR, rather than the hypothesized competition, was observed for the six OP esters and in a concentration-dependent manner. For example, T4-hTTR binding was significantly increased at concentrations of TBOEP as low as 64 nM, and up to 184% of controls at 5000 nM. A plausible explanation of these results, which to our knowledge has not been previously reported, may be allosteric interactions of the OP esters with hTTR allowing T4 to access the second site of the TH binding pocket.These in vitro results suggest a novel mechanism of OP ester toxicity via T4 binding enhancement, and possible dysregulation of T4-hTTR interactions.