Inhibition of SLC drug transporter activities by environmental bisphenols

Abstract

The plastic component bisphenol A (BPA) is suspected to exert deleterious effects towards human health and targets various cellular and molecular pathways, including activity of ATP-binding cassette drug transporters. The present study was designed to determine whether BPA and some derivatives, like its substitutes bisphenol F (BPF) and bisphenol S (BPS) and the flame retardant tetrabromobisphenol A (TBBPA), may additionally interact with solute carrier (SLC) drug transporters. Activities of the various following SLC transporters were inhibited in a major way (by >60%) by 100μM bisphenols: OCT1 and MATE1 (by BPA and TBBPA), OATP1B1 (by BPA, BPF and TBBPA), OATP1B3 and NTCP (by TBBPA) and OAT3 (by BPA, BPF, BPS and TBBPA); by contrast, activities of other transporters were not impacted (MATE2-K) or were stimulated (notably OCT1 by BPS and OCT2 by BPF). Transporter inhibitions due to bisphenols were concentrations-dependent, with half maximal inhibitory concentrations (IC) ranging from 0.5μM to 73.5μM. BPA was finally shown to be not transported by OAT3, although inhibiting this transporter in a competitive manner. Taken together, these data indicate that bisphenols interact with SLC transporters, at concentration levels however rather higher than those occurring in humans in response to environmental exposure.

Inhibition of organic cation transporter (OCT) activities by carcinogenic heterocyclic aromatic amines

“…In summary, HAAs were shown to inhibit activities of OCTs in vitro, without, at least for Trp-P-1 and Trp-P-2, being transported by OCT1 and OCT2. Such data support the conclusion that interactions with membrane transporters are not restricted to drugs, but also concern environmental chemical contaminants like HAAs, bisphenols (Bruyere et al, 2017) or pesticides (Bain and LeBlanc, 1996;Chedik et al, 2017). The in vivo relevance of pollutants-mediated inhibition of transporter activities remains however challenged by the fact that human exposure to most of pollutants may result in tissue and blood levels of pollutants probably too low to be active on in vivo drug transporter activities.…”

Tacrolimus diffusion across the peripheral mononuclear blood cell membrane: impact of drug transporters

“…[26]) nor BSP (OATP inhibitor according to Ref. [19]) had any impact on TAC accumulation in our experiments, suggesting that these transporters are not involved in TAC uptake in PBMC. Again, the choice of these inhibitors could be discussed since probenecid can also inhibit MRP efflux protein [27,28].…”

“…In transporter inhibition experiments, the concentration of inhibitors is a critical parameter, which can strongly impact the results. In our study, we chose the concentrations of inhibitors according to the literature and in particular according to Ki reported for P‐gp . We used concentrations above the Ki of the inhibitors for P‐gp.…”

Review of and Recommendations for Monitoring Contaminants and their Effects in the San Francisco Bay−Delta

“…Although the complete molecular mechanisms that underlie additive and synergistic effects (Pivcevic and Zaja 2006) are complex, the presence of TICs could specifically affect the net uptake and accumulation of certain environmental chemicals of interest ( Figure 5). For instance, the environmental chemicals and endocrine disruptors BPA, perfluorooctanoic acid (PFOA), and zearalenone (ZEN) have been shown to be transported by breast cancer resistance protein (BCRP) (Mazur et al 2012;Dankers et al 2013;Bruyere et al 2017) and inhibition of BCRP could, in turn, promote EDC and toxic substrate accumulation. Therefore, drug transporter inhibition is another key event -along with non-monotonic dose−response, synergism of single non-lethal concentrations of chemicals, and interaction with other environmental stressors -necessary to predict toxicity and assess the risks of environmental chemicals.…”

“…In addition, studies that evaluate how climate change affects this mixture reported that not only are alterations observed in the hypothalamic-pituitary-gonadal (HPG) axis, but Inhibition of ABC and SLC transporters can lead to higher accumulation of both the inhibiting environmental chemical and other toxic substrates otherwise expelled from the cells. (According to the results from Kleinow et al 2004;Dankers et al 2013;Nicklisch et al 2016;Bruyere et al, 2017;Chedik et al 2018) the hypothalamic-pituitary-thyroid (HPT) axis may also play a significant role. Tying together the individual AOPs for the individual compounds with and without APE/AP predictions can be made to justify in vivo mixture interactions.…”