Premium
Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)
Author(s) -
Nicklisch Sascha C.T.,
Hamdoun Amro
Publication year - 2020
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.14005
Subject(s) - transporter , allosteric regulation , function (biology) , small molecule , computational biology , biology , chemistry , biochemistry , microbiology and biotechnology , receptor , gene
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.