Sertraline inhibits the transport of <scp>PAT1</scp> substrates <i>in vivo</i> and <i>in vitro</i>

Nielsen, Carsten Uhd; Frølund, Sidsel; Abdulhadi, S; Sari, H; Langthaler, L; Nøhr, Martha Kampp; Kall, Morten A.; Brodin, Birger; Holm, René

doi:10.1111/bph.12341

Cited by 8 publications

(6 citation statements)

References 39 publications

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“…To our knowledge, E2 and E-E2 are the most potent PAT1 inhibitors reported in the literature with affinities approximately 3e20 times higher than sertraline. 26 Moreover, the effect of E2 appeared within 5 min and could be rapidly washed out over a 15 min period, which suggested a direct and non-genomic interaction. In other shortterm experiments, E2 has been shown to inhibit transport via other membrane transport proteins: In striatal synaptosomes from ovariectomized Sprague Dawley rats, E2 decreased dopamine uptake in a competitive manner with an IC 50 value of 7.2 ± 0.6 mM, 36 E2 inhibited L-type Ca 2þ channels in A7r5 cells with an IC 50 value of 14.24 ± 0.05 mM, 37 and non-competitively inhibited mouse 5-HT 3 receptors with an IC 50 value of 33.2 mM.…”

Section: Discussionmentioning

confidence: 95%

“…22 Generally, one substrate may competitively inhibit the transport of another substrate, but a number of inhibitors for PAT1 have also been identified such as serotonin, L-tryptophan and 5-hydroxy-tryptophan (IC 50 of 5.9, 4.7 and 0.9 mM), 24 dipeptides such as Gly-Tyr, Gly-Pro, and Gly-Phe (IC 50 of approx. 30e50 mM), 25 and the anti-depressant sertraline (IC 50 of 177e241 mM), 26 opening the possibility of both food components and drug substances having the potential to alter PAT1mediated (victim) bioavailability. In oocytes injected with PAT1 cRNA it has been proposed that 17-a-estradiol and 17-b-estradiol decrease glycine induced inward currents at concentrations of 100 mM.…”

Section: Introductionmentioning

confidence: 99%

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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

Nielsen

Pedersen

Müller

et al. 2021

Journal of Pharmaceutical Sciences

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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.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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

Nielsen

Pedersen

Müller

et al. 2021

Journal of Pharmaceutical Sciences

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“…By contrast, tryptophan derivatives such as serotonin and 5-hydroxy-L-tryptohpan are non-transported competitive inhibitors of SLC36A1 [ 57 ]. Furthermore, a selective serotonin reuptake inhibitor, sertraline, inhibits SLC36A1 activity [ 58 ]. In addition, the SLC36A1 mRNA level is increased in the jejunum of high fat diet-fed mice [ 59 ], and the transcriptional activity of SLC36A1 is up-regulated by insulin in skeletal muscle cells [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder

et al. 2016

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We investigated transcriptomic markers of late-onset major depressive disorder (LOD; onset age of first depressive episode ≥ 50 years) from the genes expressed in blood cells and identified state-dependent transcriptomic markers in these patients. We assessed the genes expressed in blood cells by microarray and found that the expression levels of 3,066 probes were state-dependently changed in the blood cells of patients with LOD. To select potential candidates from those probes, we assessed the genes expressed in the blood of an animal model of depression, ovariectomized female mice exposed to chronic ultra-mild stress, by microarray and cross-matched the differentially expressed genes between the patients and the model mice. We identified 14 differentially expressed genes that were similarly changed in both patients and the model mice. By assessing statistical significance using real-time quantitative PCR (RT-qPCR), the following 4 genes were selected as candidates: cell death-inducing DFFA-like effector c (CIDEC), ribonuclease 1 (RNASE1), solute carrier family 36 member-1 (SLC36A1), and serine/threonine/tyrosine interacting-like 1 (STYXL1). The discriminating ability of these 4 candidate genes was evaluated in an independent cohort that was validated. Among them, CIDEC showed the greatest discriminant validity (sensitivity 91.3% and specificity 87.5%). Thus, these 4 biomarkers should be helpful for properly diagnosing LOD.

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“…While the amino acid inhibitors had a similar affinity to the normal substrates, the dipeptides had a much lower affinity. Later, high-affinity inhibitors such as the anti-depressant sertraline (IC 50 of 177–241 µM, Figure 6 ) [ 266 ] and 17-α-estradiol and 17-β-estradiol (E2, Figure 6 ) were identified [ 267 ]. 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 ].…”

Section: Proton-coupled Amino Acid Transporter 1 (Pat1)mentioning

confidence: 99%

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

Jakobsen,

Nielsen

2024

Pharmaceutics

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Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the growth and development of cancer. Naturally, this has made amino acid transporters a novel target of interest for the development of new anticancer drugs. Many attempts have been made to develop inhibitors of amino acid transporters to slow down cancer cell growth, and some have even reached clinical trials. The purpose of this review is to help organize the available information on the efforts to discover amino acid transporter inhibitors by focusing on the amino acid transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), xCT (SLC7A11), SNAT1 (SLC38A1), SNAT2 (SLC38A2), and PAT1 (SLC36A1). We discuss the function of the transporters, their implication in cancer, their known inhibitors, issues regarding selective inhibitors, and the efforts and strategies of discovering inhibitors. The goal is to encourage researchers to continue the search and development within the field of cancer treatment research targeting amino acid transporters.

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Sertraline inhibits the transport of PAT1 substrates in vivo and in vitro

Cited by 8 publications

References 39 publications

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

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

Blood Transcriptomic Markers in Patients with Late-Onset Major Depressive Disorder

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

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