title: The effects of hexavalent chromium on thioredoxin reductase and peroxiredoxins in human bronchial epithelial cells.
abstract: Inhalational exposure to hexavalent chromium (Cr(VI)) compounds (e.g., chromates) is of concern in many Cr-related industries and their surrounding environments. The bronchial epithelium is directly exposed to inhaled Cr(VI). Cr(VI) species gain easy access inside cells, where they are reduced to reactive Cr species, which may also contribute to the generation of reactive oxygen species. The thioredoxin (Trx) system promotes cell survival and has a major role in maintaining intracellular thiol redox balance. Previous studies with normal human bronchial epithelial cells (BEAS-2B) demonstrated that chromates cause dose- and time-dependent oxidation of Trx1 and Trx2. The Trx's keep many intracellular proteins reduced, including the peroxiredoxins (Prx's). Prx1 (cytosolic) and Prx3 (mitochondrial) were oxidized by Cr(VI) treatments that oxidized all, or nearly all, of the respective Trx's. Prx oxidation is therefore probably the result of a lack of reducing equivalents from Trx. Trx reductases (TrxR's) keep the Trx's largely in the reduced state. Cr(VI) caused pronounced inhibition of TrxR, but the levels of TrxR protein remained unchanged. The inhibition of TrxR was not reversed by removal of residual Cr(VI) or by NADPH, the endogenous electron donor for TrxR. In contrast, the oxidation of Trx1, Trx2, and Prx3 was reversible by disulfide reductants. Prolonged inhibition of TrxR in Cr(VI)-treated cells might contribute to the sustained oxidation of Trx's and Prx's. Reduced Trx binds to an N-terminal domain of apoptosis signaling kinase (ASK1), keeping ASK1 inactive. Cr(VI) treatments that significantly oxidized Trx1 resulted in pronounced dissociation of Trx1 from ASK1. Overall, the effects of Cr(VI) on the redox state and function of the Trx's, Prx's, and TrxR in the bronchial epithelium could have important implications for redox-sensitive cell signaling and tolerance of oxidant insults.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Myers
authors.forename: Charles R
authors.initials: CR
authors.lastname: Myers
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology; D002478:Cells, Cultured; D002857:Chromium / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D010084:Oxidation-Reduction; D054464:Peroxiredoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002857:Chromium; C074702:chromium hexavalent ion; D054464:Peroxiredoxins; D013880:Thioredoxin-Disulfide Reductase
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