Disruption of small molecule transporter systems by Transporter‐Interfering Chemicals (TICs)

Abstract

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.

Transporter-interfering chemicals inhibit P-glycoprotein of yellowfin tuna (Thunnus albacares)

“…3). The ATPase assay can be conducted in activation mode to identify possible transporter substrates and in inhibition mode to identify both compounds that block transporter activity or do only weakly interact (Nicklisch and Hamdoun, 2020). Consistent to what was found with mouse ABCB1a (Nicklisch et al, 2016), all TICs inhibited verapamil-stimulated Ta-ABCB1 ATPase activity (Fig.…”

“…The co-crystal structure of mouse ABCB1a with BDE-100 revealed an intricate network of transporter:environmental chemical interactions, mediated by eleven hydrophobic and four hydrophilic amino acids (Nicklisch et al, 2016;Nicklisch and Hamdoun, 2020). Ten of these fifteen interacting residues are different from known ABCB1 inhibitor interaction sites and have not been described before (Table S3), indicating that environmental chemicals inhibit ABCB1 function by a novel…”

“…A challenge of cellular assays of transporter activity against pollutants is the confounding effect of background transporters (Nicklisch and Hamdoun, 2020). To address this issue and better characterize the activity of Ta-ABCB1 against pollutants we expressed the protein at mg scale in yeast (Pichia pastoris) and purified it using combined affinity tag and size exclusion chromatography.…”

“…These conserved proteins evolved to protect against toxic foreign molecules in diet and the environment. Among XTs, several ATP-binding cassette (ABC) transporters including ABCB1 (P-glycoprotein), ABCC1, and ABCG2, are ubiquitously expressed in biological barriers, including kidney, liver, brain and intestine, and act to limit the cellular entry and accumulation of diverse xenobiotics by binding and effluxing them (Dean et al, 2001;Giacomini et al, 2010;Nicklisch and Hamdoun, 2020). P-glycoprotein or ABCB1 is a major determinant of human drug disposition.…”

The incredible diversity of structures and functions of ABC transporters

“…One example includes the perturbation of xenobiotic transporting ABCs, such as ABCB1, by ubiquitous environmental pollutants. These transporter interfering chemicals could represent a new class of environmental toxicants that exert their effects by interfering with transporter networks [30,31].…”