Inhibitory Effects of 17-α-Ethinyl-Estradiol and 17-β-Estradiol on Transport Via the Intestinal Proton-Coupled Amino Acid Transporter (PAT1) Investigated In Vitro and In Vivo

Abstract

The proton-coupled amino acid transporter, PAT1, is known to be responsible for intestinal absorption drug substances such as gaboxadol and vigabatrin. The aim of the present study was to investigate, if 17a-ethinyl-estradiol (E-E2) and 17-b-estradiol (E) inhibit PAT1-mediated intestinal absorption of proline and taurine in vitro in Caco-2 cells and in vivo using Sprague-Dawley rats to assess the potential for taurine-drug interactions. E and E-E2 inhibited the PAT1-mediated uptake of proline and taurine in Caco-2 cells with IC 50 values of 10.0e50.0 mM without major effect on other solute carriers such as the taurine transporter (TauT), di/tri-peptide transporter (PEPT1), and serotonin transporter (SERT1). In PAT1expressing oocytes E and E-E2 were non-translocated inhibitors. In Caco-2 cells, E and E-E2 lowered the maximal uptake capacity of PAT1 in a non-competitive manner. Likewise, the transepithelial permeability of proline and taurine was reduced in presence of E and E-E2. In male Sprague Dawley rats pre-dosed with E-E2 a decreased maximal plasma concentration (C max) of taurine and increased the time (t max) to reach this was indicated, suggesting the possibility for an in vivo effect on the absorption of PAT1 substrates. In conclusion, 17-a-ethinyl-estradiol and 17-b-estradiol were identified as non-translocated and non-competitive inhibitors of PAT1.

Presence of steroid hormones in Lake Titicaca and drinking water, Puno (Peru)

“…Likewise, 17-α-ethinyl-estradiol is a non-translocating and non-competitive inhibitor of proton-coupled amino acids (Nielsen et al, 2021) being capable of inducing alterations in the endocrine system in living organisms at concentrations in the water below 1 ng L -1 (Hansen et al, 1998;Purdom et al, 1994).…”

Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches

“…Shan et al suggested that estradiol binds to PAT1 and thereby changes the conformation of the PAT1 protein from an open to a closed state, thereby decreasing transport activity [ 267 ]. Recently, Nielsen et al revisited this to assess the potential for drug-drug interactions, showing that 17-α-ethinyl-estradiol (E-E2, Figure 6 ) inhibited PAT1-mediated Pro and taurine transport in vitro in Caco-2 cells [ 268 ]. Under slightly acidic extracellular conditions, E2 and E-E2 inhibited Pro uptake with IC 50 -values of 10.0 ± 3.2 µM and 50.0 ± 14.3 µM, respectively [ 268 ].…”

“…Recently, Nielsen et al revisited this to assess the potential for drug-drug interactions, showing that 17-α-ethinyl-estradiol (E-E2, Figure 6 ) inhibited PAT1-mediated Pro and taurine transport in vitro in Caco-2 cells [ 268 ]. Under slightly acidic extracellular conditions, E2 and E-E2 inhibited Pro uptake with IC 50 -values of 10.0 ± 3.2 µM and 50.0 ± 14.3 µM, respectively [ 268 ]. The uptake of taurine was inhibited by E and E-E2 with IC 50 -values of 8.7 ± 5.1 µM and 22.9 ± 15.5 µM, respectively [ 268 ].…”

“…Under slightly acidic extracellular conditions, E2 and E-E2 inhibited Pro uptake with IC 50 -values of 10.0 ± 3.2 µM and 50.0 ± 14.3 µM, respectively [ 268 ]. The uptake of taurine was inhibited by E and E-E2 with IC 50 -values of 8.7 ± 5.1 µM and 22.9 ± 15.5 µM, respectively [ 268 ]. In contrast, the uptake of taurine via TAUT at neutral extracellular pH was not affected by E2 or E-E2 in the concentration range investigated [ 268 ].…”

Papel da insulina na captação de b-alanina pelo músculo esquelético em concentrações sub-saturantes

“…O ATB 0,+ apresenta maior afinidade para aminoácidos como a leucina e lisina do que para a β-alanina Ganapathy et al, 2008) (Fei et al, 1994). Eles também cumprem papel importante no transporte de substâncias medicamentosas, facilitando dessa forma a absorção via oral de alguns medicamentos (Nielsen et al, 2021).…”