The Effects of Hexavalent Chromium on Thioredoxin Reductase and Peroxiredoxins in Human Bronchial Epithelial Cells

ArticleinFree Radical Biology and Medicine 47(10):1477-1485 · November 2009with20 Reads
Impact Factor: 5.74 · DOI: 10.1016/j.freeradbiomed.2009.08.015

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.

    • "CSE contains hydroquinones, quinones, and semiquinone radicals, particularly, o-and p-benzosemiquinones [12,13], whereas this class of compounds invariably has a strong TrxR inhibitory capacity [9][10][11]. Chromium, mercury, and arsenic compounds have been detected in cigarette smoke [28,29], and these metal and metalloid compounds can also inhibit TrxR activity [30][31][32][33]. Harmful low molecular–weight carbonyl compounds, such as dicarbonyls including glyoxal and methylglyoxal, are formed in cigarette smoke [34]. "
    [Show abstract] [Hide abstract] ABSTRACT: The present study investigated the influence of the cigarette smoke extract (CSE) on mammalian thioredoxin reductase (TrxR) activity. TrxR is a selenoenzyme with a selenocysteine (Sec) residue exposed on the enzyme's surface. This unique Sec residue is particularly susceptible to modification by numerous types of electrophiles, leading to inactivation of TrxR and consequent cytotoxicity. Cigarette smoke contains various electrophiles, and the present study showed that CSE could inhibit intracellular TrxR through causing crosslinking and alkylation of TrxR1. TrxR inhibitory capacities of various CSEs were evaluated by using mouse-liver homogenate. Among the CSEs prepared from 18 commercial cigarette brands, TrxR inhibitory capacities of the maximum and the minimum had a 2.5-fold difference. Importantly, CSE's inhibitory capacity greatly paralleled its cytotoxic potency in all cell lines used. Compared to cytotoxic assays, which have been widely used for evaluating cigarette toxicity but are not suitable for simultaneously examining a large number of cigarette samples, the present method was simple and rapid with a high-throughput feature and thus could be used as an auxiliary means to predict the cytotoxicity of a large number of cigarette samples, making it possible to extensively screen numerous agricultural and industrial measures that potentially affect cigarette safety.
    Preview · Article · Mar 2016 · International Journal of Environmental Research and Public Health
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    • "Redox western blots for Prx1 and Prx3 were done as adapted from Cox et al.[53]as previously described[54]. Cells grown for two days in T-25 asks were fed with fresh medium and then treated with the indicated drugs or vehicle controls. "
    [Show abstract] [Hide abstract] ABSTRACT: Peroxiredoxin-3 (Prx3) accounts for about 90% of mitochondrial peroxidase activity, and its marked upregulation in many cancers is important for cell survival. Prx3 oxidation can critically alter peroxide signaling and defense and can be a seminal event in promoting cell death. Here it is shown that this mechanism can be exploited pharmacologically by combinations of clinically available drugs that compromise Prx3 function in different ways. Clinically relevant levels of the thiosemicarbazone iron chelators triapine (Tp) and 2,2'-Dipyridyl-N,N-dimethylsemicarbazone (Dp44mT) promote selective oxidation of mitochondrial Prx3, but not cytosolic Prx1, in multiple human lung and ovarian cancer lines. Decreased cell survival closely correlates with Prx3 oxidation. However, Prx3 oxidation is not merely an indicator of cell death as cytotoxic concentrations of cisplatin do not cause Prx3 oxidation. The siRNA-mediated suppression of either Prx3 or thioredoxin-2, which supports Prx3, enhances Tp's cytotoxicity. Tp-mediated Prx3 oxidation is driven by enhanced peroxide generation, but not by nitric oxide. Many tumors overexpress thioredoxin reductase (TrxR) which supports Prx activity. Direct inhibitors of TrxR (e.g. auranofin, cisplatin) markedly enhanced Tp's cytotoxicity, and auranofin enhanced Prx3 oxidation by low dose Tp. Together, these results support an important role for Prx3 oxidation in the cytotoxicity of Tp, and demonstrate that TrxR inhibitors can significantly enhance Tp's cytotoxicity. Thiosemicarbazone-based regimens could prove effective for targeting Prx3 in a variety of cancers.
    No preview · Article · Dec 2015 · Free Radical Biology and Medicine
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    • "With regards to identifying different occupation groups and their prioritization based on the risk of oxidative damage, management control and engineering control measures could be justified. Other studies exhibited chromium induced oxidative stress through parameters such as gluthathione-thiyl radicals (Myers & Myers, 2009), FRAP (Grass et al., 2010) and lipid peroxidation (Długosz et al., 2012). The results of this study demonstrated, blood chromium concentration and lipid peroxidation in plasma were significantly higher, however, ferric reducing ability of plasma and plasma thiol content was lower among electroplating workers compared to control group (Table 1). "
    [Show abstract] [Hide abstract] ABSTRACT: Abstract Oxidative stress is the main cause of hexavalant chromium-induced damage in chrome electroplating workers. The main goal of this study is toxicity analysis and the possibility of toxicity risk categorizing in the chrome electroplating workers based on oxidative stress parameters as prognostic variables. We assessed blood chromium levels and biomarkers of oxidative stress such as lipid peroxidation, thiol (SH) groups and antioxidant capacity of plasma. Data were subjected to principle component analysis (PCA) and artificial neuronal network (ANN) to obtain oxidative stress pattern for chrome electroplating workers. Blood chromium levels increased from 4.42 ppb to 10.6 ppb. Induction of oxidative stress was observed by increased in lipid peroxidation (22.38 ± 10.47 μM versus 14.74 ± 4.82 μM, p < 0.0008), decreased plasma antioxidant capacity (3.17 ± 1.35 μM versus 7.74 ± 4.45 μM, p < 0.0001) and plasma total thiol (SH groups) (0.21 ± 0.07 μM versus 0.45 ± 0.41 μM, p < 0.0042) in comparison to controls. Based on the oxidative parameters, two groups were identified by PCA methods. One category is workers with the risk of oxidative stress and second group is subjects with probable risk of oxidative stress induction. ANN methods can predict oxidative-risk category for assessment of toxicity induction in chrome electroplaters. The result showed multivariate modeling can be interpreted as the induced biochemical toxicity in the workers exposed to hexavalent chromium. Different occupation groups were assessed on the basis of risk level of oxidative stress which could further justify proceeding engineering control measures.
    Full-text · Article · Jun 2014 · Drug and Chemical Toxicology
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