Mechanisms of copper toxicity in <i>Saccharomyces cerevisiae</i> determined by microarray analysis

Yasokawa, Daisuke; Murata, Satomi; Kitagawa, Emiko; Iwahashi, Yumiko; Nakagawa, Ryoji; Hashido, Tazusa; Iwahashi, Hitoshi

doi:10.1002/tox.20406

Cited by 40 publications

(25 citation statements)

References 33 publications

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“…Despite its simplicity yeast cells are similar to higher eukaryotes in their biochemistry and physiology. Many studies confirm the usefulness of yeast for testing toxicity of xenobiotics including drugs (Yasokawa et al 2008; Letavayová et al 2008; Van der Heggen et al 2010). Yeast can be grown under hypoxia or even complete anoxia, which makes yeast cells especially useful for studies of oxidative stress-related mechanisms.…”

Section: Discussionmentioning

confidence: 91%

Ascorbate and thiol antioxidants abolish sensitivity of yeast Saccharomyces cerevisiae to disulfiram

2011

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Sensitivity of baker’s yeast to disulfiram (DSF) and hypersensitivity of a mutant devoid of Cu, Zn-superoxide dismutase to this compound is reported, demonstrating that yeast may be a simple convenient eukaryotic model to study the mechanism of DSF toxicity. DSF was found to induce oxidative stress in yeast cells demonstrated by increased superoxide production and decrease of cellular glutathione content. Anoxic atmosphere and hydrophilic antioxidants (ascorbate, glutathione, dithiothreitol, cysteine, and N-acetylcysteine) ameliorated DSF toxicity to yeast indicating that oxidative stress plays a critical role in the cellular action of DSF.

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Section: Discussionmentioning

confidence: 91%

Ascorbate and thiol antioxidants abolish sensitivity of yeast Saccharomyces cerevisiae to disulfiram

2011

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“…Copper is highly oxidatively active, and zinc has been reported to induce oxidative stress responses in yeast at high concentrations. 15, 16 Therefore, we examined whether hydrogen peroxide, a strong oxidant, could rescue statin growth inhibition and found that it did not. Thus, the rescue effects are not strain-or mating type-specific nor do they arise from the induction of a general oxidative stress response.…”

Section: Resultsmentioning

confidence: 99%

Suppression of statin effectiveness by copper and zinc in yeast and human cells

et al. 2011

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Summary Lovastatin and other statins inhibit HMG-CoA reductase, which carries out an early step in the sterol biosynthesis pathway. Statins lower cholesterol and are widely prescribed to prevent heart disease, but like many drugs, they can interact with nutritionally acquired metabolites. To probe these interactions, we explored the effect of a diverse library of metabolites on statin effectiveness using a Saccharomyces cerevisiae model. In yeast, treatment with lovastatin results in reduced growth. We combined lovastatin with the library of metabolites, and found that copper and zinc ions impaired the ability of the statin to inhibit yeast growth. Using an integrated genomic and metabolomic approach, we found that lovastatin plus metal synergistically upregulated some sterol biosynthesis genes. This altered pattern of gene expression resulted in greater flux through the sterol biosynthesis pathway and an increase in ergosterol levels. Each sterol intermediate level was correlated with expression of the upstream gene. Thus, the ergosterol biosynthetic response induced by statin is enhanced by copper and zinc. In cultured mammalian cells, these metals also rescued statin growth inhibition. Because copper and zinc impair the ability of statin to reduce sterol biosynthesis, dietary intake of these metals could have clinical relevance for statin treatment in humans.

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“…Such a transcriptional pattern is consistent with a previous work performed on yeast. By means of a DNA microarray, Yasokawa et al (2008) reported an up-regulation of genes encoding for Cu/Zn superoxide dismutase, metallothioneins, heat shock proteins and key components of the respiratory chain in response to Cu exposure. Concerning the results obtained at the proteic level, increasing Cu concentrations were associated with a significant decrease in CCO activity and, in contrast, with an increase in total protein concentration.…”

Section: Rouyn-noranda Area-muscle Tissuementioning

confidence: 98%

Transcriptional responses to environmental metal exposure in wild yellow perch (Perca flavescens) collected in lakes with differing environmental metal concentrations (Cd, Cu, Ni)

et al. 2009

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To investigate the mechanisms involved in metal stress in wild fish, yellow perch (Perca flavescens) were collected in eight lakes of the Rouyn-Noranda and Sudbury regions (Canada). Due to mining and smelting activities, these two regions indeed present a broad contamination gradient in metal concentrations (Cd, Cu, Zn and Ni; water, sediment and prey) and offer a unique research opportunity to investigate relationships between metal bioaccumulation and resulting deleterious effects in indigenous biota chronically exposed to metal mixtures. The expression level of genes encoding for proteins involved in metal detoxification (metallothioneins, mts), protein protection (heat shock protein-70, hsp-70), growth (insulin-like growth factor-1, igf-1), aerobic energy metabolism (cytochrome c oxydase, cco-1) and protection against oxidative stress (Cu/Zn superoxide dismutase, sod-1) were assessed in fish liver and muscle in association with protein and enzymatic assays for cytochrome c oxidase (CCO). Bioaccumulation of both Cd and Cu increased in response to higher ambient metal concentrations, but the two metals clearly have different modes of action. For Cd, changes in gene expression levels were more marked in the liver than in the dorsal muscle, whereas for Cu the opposite trend was observed. Hepatic Cd accumulation was linked to decreased cco-1 and sod-1 gene expression, whereas Cu accumulation was associated with a decrease in CCO enzymatic activity and an increase in total protein concentration and in cco-1, mts and hsp-70 gene expression levels. For Ni, no significant correlations were observed at the transcriptional level, but increasing hepatic Ni concentrations were significantly and positively correlated with protein concentrations and CCO activity. By coupling gene expression to biochemical and physiological endpoints, this work provides new insights into the mechanisms involved in metal stress and the adaptive response of fish chronically exposed to metal mixtures.

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Mechanisms of copper toxicity in Saccharomyces cerevisiae determined by microarray analysis

Cited by 40 publications

References 33 publications

Ascorbate and thiol antioxidants abolish sensitivity of yeast Saccharomyces cerevisiae to disulfiram

Ascorbate and thiol antioxidants abolish sensitivity of yeast Saccharomyces cerevisiae to disulfiram

Suppression of statin effectiveness by copper and zinc in yeast and human cells

Transcriptional responses to environmental metal exposure in wild yellow perch (Perca flavescens) collected in lakes with differing environmental metal concentrations (Cd, Cu, Ni)

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