Department of Environmental Toxicology, University of California, Davis, CA, USA.
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California, San Diego, La Jolla, CA, USA.
FEBS Lett. 2020 Dec;594(23):4158-4185. doi: 10.1002/1873-3468.14005. Epub 2020 Dec 9.
Small molecule transporters (SMTs) in the ABC and SLC families are important players in disposition of diverse endo- and xenobiotics. Interactions of environmental chemicals with these transporters were first postulated in the 1990s, and since validated in numerous in vitro and in vivo scenarios. Recent results on the co-crystal structure of ABCB1 with the flame-retardant BDE-100 demonstrate that a diverse range of man-made and natural toxic molecules, hereafter termed transporter-interfering chemicals (TICs), can directly bind to SMTs and interfere with their function. TIC-binding modes mimic those of substrates, inhibitors, modulators, inducers, and possibly stimulants through direct and allosteric mechanisms. Similarly, the effects could directly or indirectly agonize, antagonize or perhaps even prime the SMT system to alter transport function. Importantly, TICs are distinguished from drugs and pharmaceuticals that interact with transporters in that exposure is unintended and inherently variant. Here, we review the molecular mechanisms of environmental chemical interaction with SMTs, the methodological considerations for their evaluation, and the future directions for TIC discovery.
小分子转运体（SMTs）在 ABC 和 SLC 家族中是内源性和外源性物质处置的重要参与者。环境化学物质与这些转运体的相互作用最初是在 20 世纪 90 年代提出的，并在许多体外和体内场景中得到了验证。最近关于 ABCB1 与阻燃剂 BDE-100 的共晶结构的结果表明，各种各样的人造和天然有毒分子，以下称为转运体干扰化学物质（TICs），可以直接与 SMTs 结合并干扰其功能。TIC 结合模式通过直接和变构机制模拟底物、抑制剂、调节剂、诱导剂和可能的兴奋剂的结合模式。同样，这些影响可能直接或间接激动、拮抗，甚至可能使 SMT 系统启动改变转运功能。重要的是，TICs 与与转运体相互作用的药物和药物不同，因为暴露是意外的，并且固有地不同。在这里，我们综述了环境化学物质与 SMTs 相互作用的分子机制、评估它们的方法学考虑因素以及 TIC 发现的未来方向。
