Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung

Knickelbein, Roy G.; Ingbar, David H.; Seres, Tamás; Snow, Karisa B.; Johnston, Richard B.; Fayemi, Olutoyin; Gumkowski, F.; Jamieson, James D.; Warshaw, Joseph B.

doi:10.1152/ajplung.1996.270.1.l115

Cited by 23 publications

(22 citation statements)

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“…Subsequently, others have shown that GGT expression in the lung can be increased during oxidative stress caused by various agents, including the quinones (menadione, DMNQ, and TBHQ), NO 2 , and hyperoxia [25,26,30,77]. Takahashi et al [25] then showed that oxidative stress specifically induced type I GGT mRNA in Sprague-Dawley rat lungs.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxynonenal increases γ-glutamyl transpeptidase gene expression through mitogen-activated protein kinase pathways

Zhang

Dickinson

Liu

et al. 2005

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in the metabolism of glutathione. Previous studies have shown that GGT expression was increased by oxidants, but the mechanism remains unclear. In the present study, the effects of 4-hydroxy-2-nonenal (HNE), an electrophilic end product of lipid peroxidation, on GGT expression were investigated in rat lung epithelial type II (L2) cells. We demonstrated that HNE increased GGT activity and mRNA content in both time-and dose-dependent manners. Actinomycin D, an RNA transcription inhibitor, blocked HNE-stimulated increase in GGT mRNA, suggesting transcriptional regulation of GGT mRNA by HNE. Of the seven GGT mRNA transcripts known to be produced from the single rat GGT gene, we found that types I, II, and V-2 were constitutively expressed in L2 cells, but only types I and V-2 were increased by HNE. PD98059 and SB203580, relatively specific inhibitors of the ERK and the p38MAPK kinase pathway, respectively, significantly attenuated HNE induction of both GGT activity and mRNA content. In contrast, studies with JNK inhibitor I, a cell-permeable peptide, indicated that JNK was not involved in the GGT induction by HNE. We also found that GGT induction by HNE could be completely blocked by a cocktail of PD98059 and SB203580, suggesting a combined effect of ERK and p38MAPK pathways in HNE-mediated GGT induction. In conclusion, our results demonstrate that HNE increased GGT expression in rat alveolar type II cells and that the induction of GGT by HNE was mediated through activation of the ERK and p38MAPK pathways.

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Section: Discussionmentioning

confidence: 99%

4-Hydroxynonenal increases γ-glutamyl transpeptidase gene expression through mitogen-activated protein kinase pathways

Zhang

Dickinson

Liu

et al. 2005

Free Radical Biology and Medicine

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“…The data also suggest that HNE could induce GGT mRNA V expression via this EpRE. Based on the evidence that GGT mRNA V-2 is abundant in the lung and that the induction of mRNA V-2 is through EpRE, it can be inferred that EpRE/Nrf2 signaling is at least partially involved in GGT induction by other oxidative stress generators, including the redox-cycling quinones [11][12][13][14], NO 2 [10], and hyperoxia [15]. Because every investigated type of oxidative stress results in increased HNE production [41,88], the underlying mechanism of GGT induction by these agents likely involves the production of the common inducer HNE.…”

Section: Discussionmentioning

confidence: 99%

“…These substances include aflatoxin B1 [9], NO 2 [10], redox cycling quinones [11][12][13][14], and hyperoxia [15]. Induction of GGT by oxidative stress facilitates GSH turnover, de novo GSH synthesis, and the metabolism and detoxification of GSH conjugates and therefore is an important adaptive response that protects cells from oxidative and xenobiotic injury.…”

Section: Introductionmentioning

confidence: 99%

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

Zhang

Liu

Dickinson

et al. 2006

Free Radical Biology and Medicine

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Abstractγ-Glutamyl transpeptidase (GGT) plays key roles in glutathione homeostasis and metabolism of glutathione S-conjugates. Rat GGT is transcribed via five tandemly arranged promoters into seven transcripts. The transcription of mRNAV is controlled by promoter 5. Previously we found that GGT mRNAV-2 was responsible for the induction of GGT in rat alveolar epithelial cells by 4-hydroxynonenal (HNE). In the current study, the underlying mechanism was investigated. Reporter deletion and mutation analysis demonstrated that an electrophile-response element (EpRE) in the proximal region of GGT promoter 5 (GP5) was responsible for the basal-and HNE-induced promoter activity. Gel-shift assays showed an increased binding activity of GP5 EpRE after HNE exposure. The nuclear content of NF-E2-related factor 2 (Nrf2) was significantly increased by HNE. The recruitment of Nrf2 to GP5 EpRE after HNE treatment was demonstrated by supershift and chromatin immunoprecipitation assays. The tissue expression pattern of GGT mRNA V was previously unknown. Using polymerase chain reaction, we found that GGT mRNAV-2 was expressed in many tissues in rat. Taken together, GGT mRNAV-2 is widely expressed in rat tissues and its basal and HNE-induced expression is mediated through EpRE/Nrf2 signaling.

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“…Acivicin (500 M; 10-min preincubation) was used for estimating the extent of radiolabeled thiol uptake mediated by GGT, which cleaves GSH to glutamate and cysteinylglycine (19). Experiments were performed in Na ϩ -HEPES and Na ϩ -free HEPES buffers; results were equivalent.…”

Section: Amino Acid and Gsh Uptakementioning

confidence: 99%

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

Seres

Knickelbein

Warshaw

et al. 2000

The Journal of Immunology

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During the phagocytic respiratory burst, oxygen is converted to potent cytotoxic oxidants. Monocytes and macrophages are potentially long-lived, and we have hypothesized that protective mechanisms against oxidant stress are varied and fully expressed in these cells. We report here that the respiratory burst in monocytes is accompanied by an increase in the uptake of [35S]glutathione ([35S]GSH) after 20–30 min to levels up to 10-fold greater than those at baseline. By 30 min, 49% of the cell-associated radioactivity was in the cytosol, 41% was in membrane, and 10% was associated with the nuclear fraction. GSH uptake was inhibited by catalase, which removes hydrogen peroxide (H2O2), and micromolar H2O2 stimulated GSH uptake effectively in monocytes and also lymphocytes. Oxidation of GSH to glutathione disulfide with H2O2 and glutathione peroxidase prevented uptake. Acivicin, which inhibits GSH breakdown by γ-glutamyl transpeptidase (GGT), had no effect on the enhanced uptake seen during the respiratory burst. Uptake of cysteine or cystine, possible products of GGT activity, stayed the same or decreased during the respiratory burst. These results suggest that a GGT-independent mechanism is responsible for the enhanced GSH uptake seen during the respiratory burst. We describe here a sodium-independent, methionine-inhibitable transport system with a Km (8.5 μM) for GSH approximating the plasma GSH concentration. These results suggest that monocytes have a specific GSH transporter that is triggered by the release of H2O2 during the respiratory burst and that induces the uptake of GSH into the cell. Such a mechanism has the potential to protect the phagocyte against oxidant damage.

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Hyperoxia enhances expression of gamma-glutamyl transpeptidase and increases protein S-glutathiolation in rat lung

Cited by 23 publications

References 0 publications

4-Hydroxynonenal increases γ-glutamyl transpeptidase gene expression through mitogen-activated protein kinase pathways

4-Hydroxynonenal increases γ-glutamyl transpeptidase gene expression through mitogen-activated protein kinase pathways

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

The Phagocytosis-Associated Respiratory Burst in Human Monocytes Is Associated with Increased Uptake of Glutathione

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