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  1. Article ; Online: Regulation of Transporters for Organic Cations by High Glucose.

    Steinbüchel, Martin / Menne, Johannes / Schröter, Rita / Neugebauer, Ute / Schlatter, Eberhard / Ciarimboli, Giuliano

    International journal of molecular sciences

    2023  Volume 24, Issue 18

    Abstract: Endogenous positively charged organic substances, including neurotransmitters and cationic uremic toxins, as well as exogenous organic cations such as the anti-diabetic medication metformin, serve as substrates for organic cation transporters (OCTs) and ... ...

    Abstract Endogenous positively charged organic substances, including neurotransmitters and cationic uremic toxins, as well as exogenous organic cations such as the anti-diabetic medication metformin, serve as substrates for organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). These proteins facilitate their transport across cell membranes. Vectorial transport through the OCT/MATE axis mediates the hepatic and renal excretion of organic cations, regulating their systemic and local concentrations. Organic cation transporters are part of the remote sensing and signaling system, whose activity can be regulated to cope with changes in the composition of extra- and intracellular fluids. Glucose, as a source of energy, can also function as a crucial signaling molecule, regulating gene expression in various organs and tissues. Its concentration in the blood may fluctuate in specific physiological and pathophysiological conditions. In this work, the regulation of the activity of organic cation transporters was measured by incubating human embryonic kidney cells stably expressing human OCT1 (hOCT1), hOCT2, or hMATE1 with high glucose concentrations (16.7 mM). Incubation with this high glucose concentration for 48 h significantly stimulated the activity of hOCT1, hOCT2, and hMATE1 by increasing their maximal velocity (V
    MeSH term(s) Humans ; Organic Cation Transport Proteins/metabolism ; Organic Cation Transporter 2/genetics ; Metformin/pharmacology ; Metformin/metabolism ; Cations/metabolism ; RNA, Messenger
    Chemical Substances Organic Cation Transport Proteins ; Organic Cation Transporter 2 ; Metformin (9100L32L2N) ; Cations ; RNA, Messenger
    Language English
    Publishing date 2023-09-13
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms241814051
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Interaction of Masitinib with Organic Cation Transporters.

    Harrach, Saliha / Haag, Jasmin / Steinbüchel, Martin / Schröter, Rita / Neugebauer, Ute / Bertrand, Jessica / Ciarimboli, Giuliano

    International journal of molecular sciences

    2022  Volume 23, Issue 22

    Abstract: Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the ... ...

    Abstract Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins-MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment.
    MeSH term(s) Humans ; Mice ; Animals ; Organic Cation Transport Proteins/metabolism ; COVID-19 ; Organic Cation Transporter 2 ; Thiazoles
    Chemical Substances Organic Cation Transport Proteins ; masitinib (M59NC4E26P) ; Organic Cation Transporter 2 ; Thiazoles
    Language English
    Publishing date 2022-11-16
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms232214189
    Database MEDical Literature Analysis and Retrieval System OnLINE

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