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.

Keywords: ABC transporter; SLC transporter; allosteric; chemosensitization; endogenous substrate competition; environmental; mixtures; signaling interference; small molecule transporter; transporter-interfering chemicals.

Figure 1:. Subcellular localizations of ABC- and SLC-type small molecule transporters in ten different biological barriers.

Apical and basolateral membrane localization of ABC and SLC transporters in the indicated cell type. The anticipated direction of substrate and co-substrate flow are marked with arrows. Tight junctions are displayed as a group of three black bars in each cell type. (A) Blood-brain-barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) [,,–230]. (B) Blood-intestine barrier (BIB) [,,–234]. (C) Blood-milk barrier (BMB) in mammary glands [–237]. (D) Blood-bile barrier (BBIB) in the liver [,,,–242]. (E) Blood-urine barrier (BUB) in the kidney [,,–246]. (F) Blood-air barrier (BAB) in lung epithelial and endothelial cells [–250]. (G) Blood-heart barrier (BHB) [–254]. (H) Blood-placenta barrier (BPB) [,,–260]. (I) Blood-testis barrier (BTB) [–266]. (J) Blood-retinal barrier (BRB) in the eye [,–270]. Note that the common names for SLC-type transporters are used and the HUGO nomenclature for ABC-type transporters (https://www.genenames.org).

Figure 2:. Similar residues in vertebrate ABCB1 interact with pharmaceutical inhibitors and the TIC and flame-retardant BDE-100.

The Venn diagram displays all residues in mouse ABCB1a that interact with flame-retardant BDE-100 and known inhibitors verapamil, QZ59-SSS and QZ59-RRR according to [105] and [271]. Residues marked with an asterisk represent the “lower” binding site of QZ59-SSS. Residues marked in red are assumed to be involved in inhibition of ATP hydrolysis and transport function according to [204]. The amino acid alignment shows that 11 (marked in blue and red) of the 15 residues interacting with BDE-100 are conserved across model vertebrate species.