@article{MTMT:34719089, title = {The 2-aminoethyl diphenylborinate-based fluorescent method identifies quercetin and luteolin metabolites as substrates of Organic anion transporting polypeptides, OATP1B1 and OATP2B1}, url = {https://m2.mtmt.hu/api/publication/34719089}, author = {Kaci, Hana and Bakos, Éva and Needs, Paul W. and Kroon, Paul A. and Valentová, Kateřina and Poór, Miklós and Laczka, Csilla}, doi = {10.1016/j.ejps.2024.106740}, journal-iso = {EUR J PHARM SCI}, journal = {EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES}, unique-id = {34719089}, issn = {0928-0987}, abstract = {Organic anion transporting polypeptides (OATPs), OATP1B1 and OATP2B1 are membrane proteins mediating the cellular uptake of chemically diverse organic compounds. OATP1B1 is exclusively expressed in hepatocytes and plays a key role in hepatic detoxification. The ubiquitously expressed OATP2B1 promotes the intestinal absorption of orally administered drugs. Flavonoids are widely found in foods and beverages, and many of them can inhibit OATP function, resulting in food-drug interactions. In our previous work, we have shown that not only luteolin (LUT) and quercetin (Q), but also some of their metabolites can inhibit OATP1B1 and OATP2B1 activity. However, data about the potential direct transport of these flavonoids by OATPs have been incomplete. Hence, in the current study, we developed a simple, fluorescence-based method for the measurement of intracellular flavonoid levels. The method applies a cell-permeable small molecule (2-aminoethyl diphenylborinate, 2-APB), that, upon forming a complex with flavonoids, results in their fluorescence enhancement. This way the direct uptake of LUT and Q, and also their metabolites could be investigated both by confocal microscopy and in a fluorescence plate reader in living cells. With this approach we identified quercetin-3'-O-sulfate, luteolin-3'-O-glucuronide, luteolin-7-O-glucuronide and luteolin-3'-O-sulfate as substrates of both OATP1B1 and OATP2B1. Our results highlight that OATP1B1 and OATP2B1 can be key participants in the transmembrane movement of cell-permeable LUT and Q conjugates with otherwise low cell permeability. In addition, the novel method developed in this study can be a good completion to existing fluorescence-based assays to investigate OATP function.}, year = {2024}, eissn = {1879-0720} } @article{MTMT:34575448, title = {Interaction of mycotoxins zearalenone, α-zearalenol, and β-zearalenol with cytochrome P450 (CYP1A2, 2C9, 2C19, 2D6, and 3A4) enzymes and organic anion transporting polypeptides (OATP1A2, OATP1B1, OATP1B3, and OATP2B1)}, url = {https://m2.mtmt.hu/api/publication/34575448}, author = {Kaci, Hana and Dombi, Ágnes and Gömbös, Patrik and Szabó, András and Bakos, Éva and Laczka, Csilla and Poór, Miklós}, doi = {10.1016/j.tiv.2024.105789}, journal-iso = {TOXICOL IN VITRO}, journal = {TOXICOLOGY IN VITRO}, volume = {96}, unique-id = {34575448}, issn = {0887-2333}, keywords = {ZEARALENONE; Cytochrome P450 enzymes; organic anion transporting polypeptides; α-zearalenol; β-zearalenol}, year = {2024}, eissn = {1879-3177}, orcid-numbers = {Szabó, András/0000-0002-5315-0024} } @article{MTMT:34173508, title = {The fluorescence‐based competitive counterflow assay developed for organic anion transporting polypeptides 1A2 , 1B1 , 1B3 and 2B1 identifies pentamidine as a selective OATP1A2 substrate}, url = {https://m2.mtmt.hu/api/publication/34173508}, author = {Ungvári, Orsolya and Bakos, Éva and Kovacsics, Daniella and Laczka, Csilla}, doi = {10.1096/fj.202300530RR}, journal-iso = {FASEB J}, journal = {FASEB JOURNAL}, volume = {37}, unique-id = {34173508}, issn = {0892-6638}, abstract = {Organic anion transporting polypeptides OATP1A2, OATP1B1, OATP1B3 and OATP2B1 are Na + ‐ and ATP‐independent exchangers of large, organic compounds, encompassing structurally diverse xenobiotics, including various drugs. These OATPs influence intestinal absorption (OATP2B1), hepatic clearance (OATP1B1/3) and blood to brain penetration (OATP1A2, OATP2B1) of their drug substrates. Consequently, OATP‐mediated drug or food interactions may lead to altered pharmacokinetics and toxicity. During drug development, investigation of hepatic OATP1B1 and OATP1B3 is recommended by international regulatory agencies. Most frequently, OATP‐drug interactions are investigated in an indirect assay, i.e., by examining uptake inhibition of a radioactive or fluorescent probe. However, indirect assays do not distinguish between transported substrates and non‐transported OATP inhibitors. To fill this hiatus, a novel assay, termed competitive counterflow (CCF) has been developed and has since been applied for several OATPs to differentiate between substrates and non‐transported inhibitors. However, previous OATP CCF assays, with the exception of that for OATP1B1, used radioactive probes. In the current study, we demonstrate that sulforhodamine 101 or pyranine can be used as fluorescent probes in a CCF assay to identify transported substrates of OATP1A2, or OATPs 1B1, 1B3 and 2B1, respectively. With the help of the newly developed fluorescence‐based CCF method, we identify the FDA‐approved anti‐protozoal drug, pentamidine as a unique substrate of OATP1A2. Furthermore, we confirm the selective, OATP1A2‐mediated uptake of pentamidine in a cytotoxicity assay. Based on our results, OATP1A2 may be an important determinant of pentamidine transport through the blood–brain barrier.}, year = {2023}, eissn = {1530-6860} } @article{MTMT:34095016, title = {Interactions of the Anti-SARS-CoV-2 Agents Molnupiravir and Nirmatrelvir/Paxlovid with Human Drug Transporters}, url = {https://m2.mtmt.hu/api/publication/34095016}, author = {Bakos, Éva and Temesszentandrási-Ambrus, Csilla and Laczka, Csilla and Gáborik, Z. and Sarkadi, Balázs and Telbisz, Ágnes Mária}, doi = {10.3390/ijms241411237}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34095016}, issn = {1661-6596}, abstract = {Orally administered small molecules may have important therapeutic potential in treating COVID-19 disease. The recently developed antiviral agents, Molnupiravir and Nirmatrelvir, have been reported to be efficient treatments, with only moderate side effects, especially when applied in the early phases of this disease. However, drug–drug and drug–transporter interactions have already been noted by the drug development companies and in the application notes. In the present work, we have studied some of the key human transporters interacting with these agents. The nucleoside analog Molnupiravir (EIDD-2801) and its main metabolite (EIDD-1931) were found to inhibit CNT1,2 in addition to the ENT1,2 nucleoside transporters; however, it did not significantly influence the relevant OATP transporters or the ABCC4 nucleoside efflux transporter. The active component of Paxlovid (PF-07321332, Nirmatrelvir) inhibited the function of several OATPs and of ABCB1 but did not affect ABCG2. However, significant inhibition was observed only at high concentrations of Nirmatrelvir and probably did not occur in vivo. Paxlovid, as used in the clinic, is a combination of Nirmatrelvir (viral protease inhibitor) and Ritonavir (a “booster” inhibitor of Nirmatrelvir metabolism). Ritonavir is known to inhibit several drug transporters; therefore, we have examined these compounds together, in relevant concentrations and ratios. No additional inhibitory effect of Nirmatrelvir was observed compared to the strong transporter inhibition caused by Ritonavir. Our current in vitro results should help to estimate the potential drug–drug interactions of these newly developed agents during COVID-19 treatment. © 2023 by the authors.}, keywords = {ABC transporter; OATP; CNT; ENT; COVID-19; molnupiravir; Nirmatrelvir; Paxlovid}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Temesszentandrási-Ambrus, Csilla/0000-0002-1348-8725; Sarkadi, Balázs/0000-0003-0592-4539; Telbisz, Ágnes Mária/0000-0003-0972-4606} } @article{MTMT:34067941, title = {Synthesis and in vitro photodynamic activity of aza-BODIPY-based photosensitizers}, url = {https://m2.mtmt.hu/api/publication/34067941}, author = {Hlogyik, Tamás and Laczkó-Rigó, Réka and Bakos, Éva and Poór, Miklós and Kele, Zoltán and Laczka, Csilla and Mernyák, Erzsébet}, doi = {10.1039/d3ob00699a}, journal-iso = {ORG BIOMOL CHEM}, journal = {ORGANIC & BIOMOLECULAR CHEMISTRY}, volume = {21}, unique-id = {34067941}, issn = {1477-0520}, abstract = {Aza-BODIPY dyes have recently come to attention owing to their excellent chemical and photophysical properties. In particular, their absorption and emission maxima can efficiently be shifted to the red or even to the NIR spectral region. On this basis, aza-BODIPY derivatives are widely investigated as fluorescent probes or phototherapeutic agents. Here we report the synthesis of a set of novel aza-BODIPY derivatives as potential photosensitizers for use in photodynamic therapy. Triazolyl derivatives were obtained via Cu(I)-catalyzed azide-alkyne cycloaddition as the key step. In vitro photodynamic activities of the newly synthesized compounds were evaluated on the A431 human epidermoid carcinoma cell line. Structural differences influenced the light-induced toxicity of the test compounds markedly. Compared to the initial tetraphenyl aza-BODIPY derivative, the compound bearing two hydrophilic triethylene glycol side chains showed substantial, more than 250-fold, photodynamic activity with no dark toxicity. Our newly synthesized aza-BODIPY derivative, acting in the nanomolar range, might serve as a promising candidate for the design of more active and selective photosensitizers.}, year = {2023}, eissn = {1477-0539}, pages = {6018-6027}, orcid-numbers = {Kele, Zoltán/0000-0002-4401-0302; Mernyák, Erzsébet/0000-0003-4494-1817} } @article{MTMT:33688209, title = {Organic anion transporting polypeptide 3A1 (OATP3A1)-gated bioorthogonal labeling of intracellular proteins}, url = {https://m2.mtmt.hu/api/publication/33688209}, author = {Németh, Krisztina and László, Zsófia and Biró, Adrienn and Szatmári, Ágnes and Cserép, Balázs Gergely and Várady, György and Bakos, Éva and Laczka, Csilla and Kele, Péter}, doi = {10.3390/molecules28062521}, journal-iso = {MOLECULES}, journal = {MOLECULES}, volume = {28}, unique-id = {33688209}, issn = {1420-3049}, abstract = {Organic anion transporting polypeptides (OATPs) were found to readily deliver membrane impermeable, tetrazine bearing fluorescent probes into cells. This feature was explored in OATP3A1 conditioned bio-orthogonal labeling schemes of various intracellular proteins in live cells. Confocal microscopy and super-resolution microscopy (STED) studies have shown that highly specific and efficient staining of the selected intracellular proteins can be achieved with the otherwise non-permeable probes when OATP3A1 is present in the cell membrane of cells. Such a transport protein linked bio-orthogonal labeling scheme is believed to be useful in OATP3A1 activity-controlled protein expression studies in the future. © 2023 by the authors.}, keywords = {PROTEINS; PROTEIN; Organic Anion Transporters; Flow Cytometry; Fluorescent Dyes; fluorescent dye; confocal microscopy; organic anion transporter; super-resolution microscopy; Cell permeability; Intracellular labeling; large Stokes shift fluorescent probes; live cell bio-orthogonal modification; organic anion transporter polypeptide 3A1; self-labeling enzyme tags}, year = {2023}, eissn = {1420-3049}, orcid-numbers = {Szatmári, Ágnes/0000-0001-8768-8212; Cserép, Balázs Gergely/0000-0002-0779-0338; Várady, György/0000-0003-2012-9680} } @article{MTMT:33633514, title = {Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox}, url = {https://m2.mtmt.hu/api/publication/33633514}, author = {Laczka, Csilla and Ungvári, Orsolya and Bakos, Éva}, doi = {10.1016/j.bcp.2023.115448}, journal-iso = {BIOCHEMIC PHARMACOL}, journal = {BIOCHEMICAL PHARMACOLOGY}, volume = {209}, unique-id = {33633514}, issn = {0006-2952}, year = {2023}, eissn = {1873-2968} } @article{MTMT:33547988, title = {Interactions of Mycotoxin Alternariol with Cytochrome P450 Enzymes and OATP Transporters}, url = {https://m2.mtmt.hu/api/publication/33547988}, author = {Fliszár-Nyúl, Eszter and Ungvári, Orsolya and Dombi, Ágnes and Laczka, Csilla and Poór, Miklós}, doi = {10.3390/metabo13010045}, journal-iso = {METABOLITES}, journal = {METABOLITES}, volume = {13}, unique-id = {33547988}, issn = {2218-1989}, abstract = {Alternariol (AOH) is an emerging mycotoxin produced by Alternaria strains. The acute toxicity of the mycotoxin is low; however, chronic exposure to AOH may result in the development of endocrine disruptor and/or carcinogenic effects. The toxicokinetic properties of AOH have barely been characterized. Therefore, in this study, we aimed to investigate its interactions with CYP (1A2, 2C9, 2C19, 2D6, and 3A4) enzymes and OATP (1A2, 1B1, 1B3, and 2B1) transporters employing in vitro enzyme assays and OATP overexpressing cells, respectively. Our results demonstrated that AOH is a strong inhibitor of CYP1A2 (IC50 = 0.15 μM) and CYP2C9 (IC50 = 7.4 μM). Based on the AOH depletion assays in the presence of CYP enzymes, CYP1A2 is mainly involved, while CYP2C19 is moderately involved in the CYP-catalyzed biotransformation of the mycotoxin. AOH proved to be a strong inhibitor of each OATP transporter examined (IC50 = 1.9 to 5.4 μM). In addition, both direct and indirect assays suggest the involvement of OATP1B1 in the cellular uptake of the mycotoxin. These findings promote the deeper understanding of certain toxicokinetic interactions of AOH.}, year = {2023}, eissn = {2218-1989}, orcid-numbers = {Fliszár-Nyúl, Eszter/0000-0003-0923-0059; Poór, Miklós/0000-0003-1425-7459} } @article{MTMT:33532438, title = {Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells}, url = {https://m2.mtmt.hu/api/publication/33532438}, author = {Pivarcsik, Tamás and Pósa, Vivien and Kovács, Hilda and May, Nóra Veronika and Spengler, Gabriella and Pósa, Szonja P. and Tóth, Szilárd and Nezafat Yazdi, Zeinab and Laczka, Csilla and Ugrai, Imre and Szatmári, István and Szakács, Gergely and Enyedy, Éva Anna}, doi = {10.3390/ijms24010593}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {33532438}, issn = {1661-6596}, abstract = {Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {May, Nóra Veronika/0000-0003-4770-4681; Spengler, Gabriella/0000-0001-8085-0950; Pósa, Szonja P./0000-0002-7535-9689; Szatmári, István/0000-0002-8571-5229; Enyedy, Éva Anna/0000-0002-8058-8128} } @article{MTMT:33294693, title = {Interaction of luteolin, naringenin, and their sulfate and glucuronide conjugates with human serum albumin, cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) enzymes and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters}, url = {https://m2.mtmt.hu/api/publication/33294693}, author = {Kaci, Hana and Bodnárová, Slávka and Fliszár-Nyúl, Eszter and Lemli, Beáta and Pelantová, Helena and Valentová, Kateřina and Bakos, Éva and Laczka, Csilla and Poór, Miklós}, doi = {10.1016/j.biopha.2022.114078}, journal-iso = {BIOMED PHARMACOTHER}, journal = {BIOMEDICINE & PHARMACOTHERAPY}, volume = {157}, unique-id = {33294693}, issn = {0753-3322}, abstract = {Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites. In this study, we aimed to investigate the interactions of the sulfate and glucuronic acid conjugates of luteolin and naringenin with human serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Our main findings are as follows: (1) Sulfate conjugates formed more stable complexes with albumin than the parent flavonoids. (2) Luteolin and naringenin conjugates showed no or only weak inhibitory action on the CYP enzymes examined. (3) Certain conjugates of luteolin and naringenin are potent inhibitors of OATP1B1 and/or OATP2B1 enzymes. (4) Conjugated metabolites of luteolin and naringenin may play an important role in the pharmacokinetic interactions of these flavonoids.}, year = {2023}, eissn = {1950-6007}, orcid-numbers = {Fliszár-Nyúl, Eszter/0000-0003-0923-0059; Lemli, Beáta/0000-0001-8903-1337} }