Functional and Molecular Effects of Mercury Compounds on the Human OCTN1 Cation Transporter: C50 and C136 Are the Targets for Potent Inhibition

作者: Michele Galluccio , Lorena Pochini , Valentina Peta , Maria Iannì , Mariafrancesca Scalise

DOI: 10.1093/TOXSCI/KFU259

关键词:

摘要: The effect of mercury compounds has been tested on the organic cation transporter, hOCTN1. MeHg þ ,H g 2þ ,o r Cd caused strong inhibition transport. 1,4-Dithioerythritol (DTE), cysteine (Cys), and N-acetyl-L-cysteine reversed (NAC) at different extents. 2-Aminoethyl methanethiosulfonate hydrobromide (MTSEA), a prototype SH reagent, exerted transport similar to that observed for mercurial agents. To investigate mechanism action mercurials, mutants hOCTN1 in which each Cys residues was substituted by Ala have constructed, overexpressed Escherichia coli, purified. Tetraethylammonium chloride (TEA) uptake mediated mutant proteoliposomes comparable wild type (WT). IC50 values WT were derived from dose-response analyses. C50A C136A showed significant increase indicating 2 involved interaction with transporter. double C50A/C136A constructed; lack confirmed are targets compounds. MTSEA behavior respect reagents difference increased also C81A mutant. Similar results obtained when measured as acetylcholine uptake. Ethyl (Thimerosal) inhibited well. C50A, and, very lower extent, C50 major target this compound. homology model built using template PiPT validated experimental data proteins.

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