Elevated Reactive Oxygen Species but not Glutathione Regulate Mercury Resistance to AML-2/DX100 Cells

Choi, Cheol-Hee; Bark, Hyun; Chung, Jae Myung; Park, Eui Kyun; Kim, Sang-Hyun

doi:10.1080/08923970600927918

Cited by 6 publications

(1 citation statement)

References 23 publications

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“…are able to induce MAPKs activities and subsequently AP-1 activity [29,44,45]. A cross-talk between the AhR and AP-1 signaling pathways has been previously reported [14,46].…”

Section: +mentioning

confidence: 72%

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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“…are able to induce MAPKs activities and subsequently AP-1 activity [29,44,45]. A cross-talk between the AhR and AP-1 signaling pathways has been previously reported [14,46].…”

Section: +mentioning

confidence: 72%

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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The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

Wiese

Stefan

2019

Medicinal Research Reviews

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Several mechanisms of pharmacokinetic, metabolic, and regulatory nature have been elucidated to take part or act in concert in the phenomenon of multidrug resistance (MDR). MDR is characterized by cross‐resistance of cells against chemotherapeutic agents, which are used for treatment of e.g., cancer, bacterial infections, or human immunodeficiency virus (HIV) infections. One group of proteins that combines all three stated aspects—the metabolism and distribution of drugs as well as their own regulation—is adenosine triphosphate‐binding cassette (ABC) transporters. These efflux pumps use the energy of adenosine triphosphate hydrolysis for drug translocation from the membrane and the cytosol to the extracellular space, often with cotransport of a cosubstrate. Multidrug resistance‐associated protein 1 (MRP1, ABCC1) had been discovered as one major key player in cancer‐related MDR. The xenobiotic substrates include anthracyclines, vinca alkaloids, podophyllotoxins, as well as glutathione (GSH)‐adducts of certain cytostatics. Contrary to other transport proteins involved in cancer‐related MDR the activity of MRP1 is related to the GSH content of cells. A modern strategy to overcome MRP1‐associated MDR is besides its inhibition the activation of GSH efflux, enforcing cell death due to cellular stress. In addition, it has recently been found that MRP1 contributes to the β‐amyloid protein clearance in Alzheimer's disease (AD). Collectively, transport activation of MRP1 is of therapeutic value, and furthermore helps to elucidate the transport protein function and the mechanisms behind it. This review is meant to summarize the known concepts of MRP1 activation, which might contribute to a further understanding of MRP1 in particular and ABC transporters in general.

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Modulation of mercury-induced mitochondria-dependent apoptosis by glycine in hepatocytes

Pal

Das

et al. 2011

Amino Acids

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Mercury (Hg) is one of the universal environmental pollutants and is responsible for various organ pathophysiology including oxidative stress-induced hepatic disorders. In the present study, we aimed to explore the protective role of glycine in Hg-induced cytotoxicity and cell death in murine hepatocytes. Exposure of mercury (20 μM), in the form HgCl2 for 1 h, significantly enhanced the ALT and ALP leakage, increased reactive oxygen species production, reduced cell viability and distorted the antioxidant status of hepatocytes. Flow cytometric analyses shows that Hg-induced apoptotic death in hepatocytes. Mechanism of this pathophysiology involves reduced mitochondrial membrane potential, variations in Bcl-2/Bad proteins, activation of caspases and cleavage of PARP protein. In addition, Hg distinctly increased NF-κB phosphorylation in association with IKKα phosphorylation and IκBα degradation. Concurrent treatment with glycine (45 mM), however, reduced Hg-induced oxidative stress, attenuated the changes in NF-κB phosphorylation and protects hepatocytes from Hg-induced apoptotic death. Hg also distinctly increased the phosphorylation of p38, JNK and ERK mitogen-activated protein kinase (MAPKs). Glycine treatment suppressed these apoptotic events, signifying its protective role in Hg-induced hepatocyte apoptosis as referred by reduction of p38, JNK and ERK MAPK signaling pathways. Results suggest that glycine can modulate Hg-induced oxidative stress and apoptosis in hepatocytes probably because of its antioxidant activity and functioning via mitochondria-dependent pathways and could be a beneficial agent in oxidative stress-mediated liver diseases.

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Elevated Reactive Oxygen Species but not Glutathione Regulate Mercury Resistance to AML-2/DX100 Cells

Cited by 6 publications

References 23 publications

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

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

The A‐B‐C of small‐molecule ABC transport protein modulators: From inhibition to activation—a case study of multidrug resistance‐associated protein 1 (ABCC1)

Modulation of mercury-induced mitochondria-dependent apoptosis by glycine in hepatocytes

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