TRANSCRIPTIONAL REGULATION OF THE NAD(P)H:QUINONE OXIDOREDUCTASE 1 AND GLUTATHIONE<i>S</i>-TRANSFERASE YA GENES BY MERCURY, LEAD, AND COPPER

Korashy, Hesham M.; El‐Kadi, Ayman O.S.

doi:10.1124/dmd.105.005397

Cited by 58 publications

(32 citation statements)

References 35 publications

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“…This response is not unique to ethanol-exposed embryos. Similar effects have been observed in cells treated with a numbers of other toxic chemicals, including heavy metals (19,23), cigarette smoke (22), and arachidonic acid (17). Of particular interest to this study is that an increase in Nrf2 protein has also been observed in livers and hepatocytes of alcohol-fed mice and rats (16).…”

Section: Discussionsupporting

confidence: 59%

Nrf2-Mediated Transcriptional Induction of Antioxidant Response in Mouse Embryos Exposed to Ethanolin vivo: Implications for the Prevention of Fetal Alcohol Spectrum Disorders

Dong

Sulik

Chen

2008

Antioxidants & Redox Signaling

202

131

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Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that is important in protection against oxidative stress. This study was designed to determine the role of Nrf2 signaling in transcriptional activation of detoxifying and antioxidant genes in an in vivo mouse fetal alcohol syndrome model. Maternal ethanol treatment was found to increase both Nrf2 protein levels and Nrf2-ARE binding in mouse embryos. It also resulted in a moderate increase in the mRNA expression of Nrf2 downstream target detoxifying and antioxidant genes as well as an increase in the expression of antioxidant proteins. Pretreatment with the Nrf2 inducer, 3H-1,2 dithiole-3-thione (D3T), significantly increased Nrf2 protein levels and Nrf2-ARE binding, and strongly induced the mRNA expression of Nrf2 downstream target genes. It also increased the expression of antioxidant proteins and the activities of the antioxidant enzymes. Additionally, D3T pretreatment resulted in a significant decrease in ethanol-induced reactive oxygen species generation and apoptosis in mouse embryos. These results demonstrate that Nrf2 signaling is involved in the induction of antioxidant response in ethanol-exposed embryos. In addition, the potency of D3T in inducing antioxidants as well as in diminishing ethanol-induced apoptosis suggests that further exploration of the antiteratogenic effect of this compound will be fruitful. Antioxid.

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Section: Discussionsupporting

confidence: 59%

Nrf2-Mediated Transcriptional Induction of Antioxidant Response in Mouse Embryos Exposed to Ethanolin vivo: Implications for the Prevention of Fetal Alcohol Spectrum Disorders

Dong

Sulik

Chen

2008

Antioxidants & Redox Signaling

202

131

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“…Recent studies from our laboratory showed that mercury (Hg 2+ ), lead (Pb 2+ ), and copper (Cu 2+ ) modulate the expression of Nqo1 gene in Hepa 1c1c7 cells through AhR/XRE-and Nrf2/ARE-dependent mechanisms [20,21]. In addition, we recently showed that all the three metals were able to induce the NF-κB and AP-1 binding activity in Hepa 1c1c7 cells [22].…”

Section: Introductionmentioning

confidence: 96%

NF‐κB and AP‐1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper

Korashy

El‐Kadi

2008

J Biochem & Molecular Tox

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We have previously shown that Hg(2+), Pb(2+), and Cu(2+), significantly modulate the expression of NAD(P):quinone oxidoreductase 1 (Nqo1) in Hepa 1c1c7 cells through oxidative stress-dependent mechanisms. In the current study, we examined the role of redox-sensitive transcription factors, NF-kappaB and AP-1 signaling pathways in the modulation of Nqo1 by heavy metals. Our results show that the depletion of cellular GSH using L-buthionine-(S,R)-sulfoximine further potentiated the heavy metal-mediated induction of Nqo1 at the mRNA and activity levels. The NF-kappaB activator, PMA, significantly abolished the metal-mediated effects on Nqo1 mRNA and activity. In parallel, the NF-kappaB inhibitor, PDTC, further potentiated the Pb(2+)- and Hg(2+)-mediated induction of Nqo1 mRNA and activity levels, respectively. Inhibition of AP-1 upstream signaling pathway such as JNK by SP600125 significantly suppressed heavy metal-mediated induction of Nqo1 mRNA and activity levels. In contrast, inhibition of ERK by U0126 further potentiated heavy metal-mediated effects on Nqo1 mRNA, while only potentiated Hg(2+)-mediated induction of Nqo1 activity. Furthermore, p38 MAPK inhibitor, SB203580 further potentiated Pb(2+)- and Cu(2+)-mediated effects at the mRNA levels, whereas did not alter the activity levels. These results clearly demonstrate that activation of NF-kappaB negatively regulates the expression of Nqo1 by heavy metals, whereas AP-1 signaling pathways differentially modulates the heavy metal-mediated effects.

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“…Heavy Metal Toxicity: In vitro exposure of mouse hepatoma cells to heavy metals including inorganic mercury and lead results in the transcriptional activation of Nqo1 and Gst genes (Korashy and El-Kadi, 2006). Similarly, arsenic induces Nqo1 in hepatoma cells by stabilizing Nrf2 protein (He et al, 2006).…”

Section: Cytochrome P450 2e1-associated Oxidative Stressmentioning

confidence: 99%

Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease

2007

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Transcription factor NF-E2-related factor 2 (Nrf2) belongs to the basic region-leucine zipper family and is activated in response to electrophiles and reactive oxygen species. Nrf2 coordinately regulates the constitutive and inducible transcription of a wide array of genes involved in drug metabolism, detoxification, and antioxidant defenses. During periods of oxidative stress, Nrf2 is released from sequestration in the cytoplasm and translocates to the nucleus. Nrf2 binds antioxidant response elements (AREs) in the regulatory regions of target genes and activates transcription. Genetically modified mice lacking Nrf2 serve as a useful tool for identifying new ARE-regulated genes and assessing the ability of Nrf2 to confer protection against a variety of pathologies in numerous organs including the liver, intestine, lung, skin, and nervous system. With regards to the liver and gastrointestinal tract, Nrf2 knockout mice are more susceptible to acetaminophen-induced hepatocellular injury, benzo[a]pyrene-induced tumor formation and Fasand TNFα-mediated hepatocellular apoptosis. The higher sensitivity of Nrf2 knockout mice to chemical toxicity is due in part to reduced basal and inducible expression of detoxification enzymes. Nrf2 may also be important in protecting against liver fibrosis, gallstone development, and formation of aberrant crypt foci. Research of Nrf2 has opened up new opportunities in understanding how antioxidant defense pathways are regulated, how oxidative stress contributes to disease progression and may serve as a novel target for designing therapies to prevent and treat diseases in which oxidative stress is implicated.

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TRANSCRIPTIONAL REGULATION OF THE NAD(P)H:QUINONE OXIDOREDUCTASE 1 AND GLUTATHIONES-TRANSFERASE YA GENES BY MERCURY, LEAD, AND COPPER

Abstract: ABSTRACT:Recently, we demonstrated the ability of heavy metals, particularly

Cited by 58 publications

References 35 publications

Nrf2-Mediated Transcriptional Induction of Antioxidant Response in Mouse Embryos Exposed to Ethanolin vivo: Implications for the Prevention of Fetal Alcohol Spectrum Disorders

Nrf2-Mediated Transcriptional Induction of Antioxidant Response in Mouse Embryos Exposed to Ethanolin vivo: Implications for the Prevention of Fetal Alcohol Spectrum Disorders

NF‐κB and AP‐1 are key signaling pathways in the modulation of NAD(P)H:Quinone oxidoreductase 1 gene by mercury, lead, and copper

Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease

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