Expression patterns and novel splicing variants of glutathione-S-transferase isoenzymes of human lung and hepatocyte cell lines

Bauer, Mario; Herbarth, Olf; Aust, Gabriela; Hengstler, Jan G.; Dotzauer, Anja; Graebsch, C.; Schmuecking, Eike

doi:10.1007/s00441-005-0150-8

Cited by 17 publications

(10 citation statements)

References 43 publications

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“…The decrease in GSTPi expression was associated with decreased total GST activity in the lungs of mice. Levels of GSTPi mRNA have been shown to correlate to GST activity in other studies (R 2 =0.77, P<0.001) 45 . GSTPi was down-regulated in Balb/c and C57Bl/6 strains of mice supporting that the observation was not restricted to a given strain.…”

Section: Discussionmentioning

confidence: 58%

Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

Schroer

Gibson

Sivaprasad

et al. 2011

Journal of Allergy and Clinical Immunology

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Background Glutathione S-transferase Pi (GSTPi) is the predominant redox regulator in the lung. While evidence implicates an important role for GSTPi in asthma, the mechanism for this has remained elusive. Objectives To determine how GSTPi is regulated in asthma and to elucidate its role in maintaining redox homeostasis. Methods We elucidated the regulation of GSTPi in children with asthma and utilized murine models of asthma to determine the role of GSTPi in redox homeostasis. Measurements and Main Results Our findings demonstrate that GSTPi transcript levels are markedly down-regulated in allergen and IL-13 treated mouse models of asthma via STAT6 dependent and independent pathways. Nuclear factor-erythroid 2 related factor 2 (Nrf2) was also down-regulated in these models. The decrease in GSTPi expression was associated with decreased total GST activity in the lungs of mice. Examination of cystine intermediates uncovered a functional role for GSTPi in regulating Cys oxidation, whereby GSTPi-deficient mice exhibited increased oxidative stress (increase in % cystine) compared with wild-type mice following allergen challenge. GSTPi expression was similarly down-regulated in children with asthma. Conclusions These data collectively suggest that down-regulation of GSTPi following allergen challenge may contribute to the asthma phenotype due to disruption of redox homeostasis and increased oxidative stress. Furthermore, GSTPi may be an important therapeutic target for asthma, and evaluation of GSTPi expression may prove beneficial in identifying individuals who would benefit from therapy targeting this pathway.

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Section: Discussionmentioning

confidence: 58%

Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

Schroer

Gibson

Sivaprasad

et al. 2011

Journal of Allergy and Clinical Immunology

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“…However, our data showing similar generation of F 2 -isoprostanes irrespective of the GSTM1 genotype do not support a substantial antioxidant role of GSTM1 in atopic asthmatic airways. In fact, GSTM1 provides only 0.1% of GST activity in normal lungs (37). Currently, it is unclear why airway inflammation in the GSTM1 1 individuals with atopic asthma is deviated toward the neutrophilic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Asthmatic Airway Neutrophilia after Allergen Challenge Is Associated with the Glutathione S-Transferase M1 Genotype

Hoskins

Reiss

et al. 2013

Am J Respir Crit Care Med

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Rationale: Asthma is a heterogeneous lung disorder characterized by airway inflammation and airway dysfunction, manifesting as hyperresponsiveness and obstruction. Glutathione S-transferase M1 (GSTM1) is a multifunctional phase II enzyme and regulator of stress-activated cellular signaling relevant to asthma pathobiology. A common homozygous deletion polymorphism of the GSTM1 gene eliminates enzyme activity. Objectives: To determine the effect of GSTM1 on airway inflammation and reactivity in adults with established atopic asthma in vivo. Methods: Nineteen GSTM1 wild-type and eighteen GSTM1-null individuals with mild atopic asthma underwent methacholine and inhaled allergen challenges, and endobronchial allergen provocations through a bronchoscope. Measurements and Main Results: The influx of inflammatory cells, panels of cytokines and chemokines linked to asthmatic inflammation, F 2 -isoprostanes (markers of oxidative stress), and IgE were measured in bronchoalveolar lavage fluid at baseline and 24 hours after allergen instillation. Individuals with asthma with the GSTM1 wild-type genotype had greater baseline and allergen-provoked airway neutrophilia and concentrations of myeloperoxidase than GSTM1-null patients. In contrast, the eosinophilic inflammation was unaffected by GSTM1. The allergen-stimulated generation of acute-stress and proneutrophilic mediators, tumor necrosis factor-a, CXCL-8, IL-1b, and IL-6, was also greater in the GSTM1 wild-type patients. Moreover, post-allergen airway concentrations of IgE and neutrophilgenerated mediators, matrix metalloproteinase-9, B-cell activating factor, transforming growth factor-b1, and elastase were higher in GSTM1 wild-type individuals with asthma. Total airway IgE correlated with B-cell activating factor concentrations. In contrast, levels of F 2 -isoprostane were comparable in both groups. Finally, GSTM1 wild-type individuals with asthma required lower threshold concentrations of allergen to produce bronchoconstriction. Conclusions: The functional GSTM1 genotype promotes neutrophilic airway inflammation in humans with atopic asthma in vivo.Keywords: atopic asthma; GSTM1 polymorphism; inflammatory asthma phenotypes; neutrophilic airway inflammation Asthma is a heterogeneous airway disorder characterized by inflammation, hyperresponsiveness, and obstruction. There is considerable interest in classifying asthma phenotypes. It has been suggested that the type of airway inflammation might define asthma phenotypes. One proposed classification uses eosinophilic, neutrophilic, and paucigranulocytic cellular inflammation to define three subtypes of asthma (1). The neutrophilic inflammation has recently drawn more attention because of its association with severe asthma and poor response to corticosteroids (2). The relationship between various asthmatic phenotypes and genotypes in humans is poorly understood.Glutathione S-transferase M1 (GSTM1) is a phase II cytoprotective protein from the family of cytosolic GSTs (3). The GSTM1 gene is located on chromosome 1p13.3 and ha...

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“…Although the ORs for GSTP1 Ile105Val and EPHX1 phenotypes were stronger in children with the GSTM1 null genotype (not shown), GSTM1 and GSTT1 null genotypes were not independently associated with asthma. GSTP1 is the predominant enzyme that contributes to the GST enzyme activity in the lungs 33. This may explain why significant associations were not found between GSTM1 and GSTT1 genotypes and asthma.…”

Section: Discussionmentioning

confidence: 99%

Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma

Salam

Lin

Avol

et al. 2007

Thorax

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Background: Microsomal epoxide hydrolase (EPHX1) metabolises xenobiotics including polyaromatic hydrocarbons (PAHs). Functional variants at this locus have been associated with respiratory diseases. The effects of EPHX1 variants may depend upon exposures from tobacco smoke and traffic emissions that contain PAHs as well as variants in other enzymes in the PAH metabolic pathway such as glutathione S-transferase (GST) genes. A study was undertaken to investigate associations of variants in EPHX1, GSTM1, GSTP1 and GSTT1 with asthma and the relationships between asthma, EPHX1 metabolic phenotypes and exposure to sources of PAHs. Methods: Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate the associations of genetic variants and exposures with asthma phenotypes using data from 3124 children from the Children's Health Study. Results: High EPHX1 activity was associated with an increased risk for lifetime asthma (OR 1.51, 95% CI 1.14 to 1.98) which varied by GSTP1 Ile105Val genotype and by residential proximity to major roads (p for interaction = 0.006 and 0.03, respectively). Among children with GSTP1 105Val/Val genotype, those who had high EPHX1 phenotype had a fourfold (95% CI 1.97 to 8.16) increased risk of lifetime asthma than children with low/intermediate EPHX1 phenotype. Among children living within 75 metres of a major road, those with high EPHX1 activity had a 3.2-fold (95% CI 1.75 to 6.00) higher lifetime asthma risk than those with low/intermediate activity. The results were similar for current, early persistent and late onset asthma. Children with high EPHX1 phenotype, GSTP1 Val/Val genotype who lived ,75 metres from a major road were at the highest asthma risk. Conclusion: EPHX1 and GSTP1 variants contribute to the occurrence of childhood asthma and increase asthma susceptibility to exposures from major roads.

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Expression patterns and novel splicing variants of glutathione-S-transferase isoenzymes of human lung and hepatocyte cell lines

Cited by 17 publications

References 43 publications

Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

Downregulation of glutathione S-transferase pi in asthma contributes to enhanced oxidative stress

Asthmatic Airway Neutrophilia after Allergen Challenge Is Associated with the Glutathione S-Transferase M1 Genotype

Microsomal epoxide hydrolase, glutathione S-transferase P1, traffic and childhood asthma

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