title: Binding of tellurium to hepatocellular selenoproteins during incubation with inorganic tellurite: consequences for the activity of selenium-dependent glutathione peroxidase.
abstract: The metallic group XVIa elements selenium and tellurium possess remarkably similar chemical properties. However, unlike selenium, tellurium is not an essential micronutrient and, indeed, induces both acute and chronic toxicity in a variety of species. Despite this, very little is known of the molecular mechanisms of toxicity of tellurium, particularly with respect to potential chemical interactions with selenium-containing components in the cell. In this work we describe a novel interaction of inorganic tellurite with hepatocellular selenoproteins, particularly with selenium-dependent glutathione peroxidase. The accumulation of (121Te)-tellurite into cultured primary rat liver hepatocytes was shown to be much more rapid than that of (75Se)-selenite on a molar basis. Neither the uptake of (121Te)-tellurite nor of (75Se)-selenite was affected by a large molar excess of the unlabelled counterpart, respectively. Interestingly, separation of the hepatocellular proteins on continuous pH denaturing gels demonstrated clear binding of radiolabelled tellurium to a number of protein bands, including one at 23 and one at 58 kDa, which corresponded to proteins readily labelled in cells treated with (75Se)-selenite. The binding of (121Te) to these proteins was insensitive to reduction with mercaptoethanol and not affected by pre-treatment of the cells with cycloheximide. When purified selenium-dependent glutathione peroxidase was treated directly with (121Te)-tellurite, the protein became labelled in an analogous manner to that achieved in intact cells. This was not affected by coincubation of the enzyme with (121Te)-tellurite and one or both of its substrates. Additionally, incubation of the peroxidase with tellurite effectively inhibited its ability to catalyse glutathione-dependent reduction of hydrogen peroxide. These data suggest that inorganic tellurite delivers tellurium to the intracellular milieu in a form capable of binding to some intracellular selenoproteins and at least in the case of glutathione peroxidase, cause inhibition of catalytic activity. The nature of the binding seems not to be due to the insertion of tellurocysteine into the protein and the insensitivity to reductive cleavage with mercaptoethanol seems to preclude the formation of stable telluro-selenides in the proteins. These data may offer alternative explanations for the established toxicity of tellurium via disruption of selenoprotein function, particularly by the induction of intracellular oxidative stress by the inhibition of Se-dependent glutathione peroxidase.
authors.affiliation: National Institute of Working Life, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Garberg
authors.forename: L
authors.initials: L
authors.lastname: Engman
authors.forename: V
authors.initials: V
authors.lastname: Tolmachev
authors.forename: H
authors.initials: H
authors.lastname: Lundqvist
authors.forename: R G
authors.initials: RG
authors.lastname: Gerdes
authors.forename: I A
authors.initials: IA
authors.lastname: Cotgreave
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism*; D011868:Radioisotopes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012643:Selenium / Q000378:metabolism*; D012644:Selenium Radioisotopes / Q000378:metabolism / Q000493:pharmacokinetics; D051140:Selenoproteins; D013691:Tellurium / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D011500:Protein Synthesis Inhibitors; D011506:Proteins; D011868:Radioisotopes; D012644:Selenium Radioisotopes; D051140:Selenoproteins; D003513:Cycloheximide; D005979:Glutathione Peroxidase; D012643:Selenium; C026660:tellurous acid; D013691:Tellurium