γ-Glutamyltranspeptidase-Dependent Metabolism of 4-Hydroxynonenal–Glutathione Conjugate

Enoiu, Milica; Herber, R.; Wennig, Robert; Marson, Claude; Bodaud, H.; Leroy, Pierre; Mitrea, Niculina; Siest, Gérard; Wellman, Maria

doi:10.1006/abbi.2001.2633

Cited by 31 publications

(34 citation statements)

References 38 publications

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“…In vitro, rat pericytes exposed to diabetic conditions, such as high glucose, AGE-lysine, and angiotensin II showed a decrease in both GPx activity and GSH levels [25]. We demonstrate here for the first time that RBCs of obese Type 2 diabetics and of hypertensive-obese Type 2 diabetics contain 4-HNE Michael adducts at the outer leaflet of membrane; 4-HNE is a toxic and very reactive aldehyde obtained from lipid peroxidation [26], that can be detoxified by conjugation with GSH [27]. Since in diabetes the concentration of GSH is diminished [5], the detoxification of 4-HNE at the surface of RBCs may be impeded.…”

Section: Discussionmentioning

confidence: 71%

Effects of ageing on carbonyl stress and antioxidant defense in RBCs of obese Type 2 diabetic patients

Constantin¹,

Constantinescu²,

Dumitrescu³

et al. 2005

J Cellular Mol Med

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In this study we investigated the effects of ageing on the carbonyl stress (protein carbonyls and 4‐hydroxy‐2‐nonenal groups) and glutathione antioxidant defense in red blood cells (RBCs) of obese Type 2 diabetic patients with/without hypertensive complications. To this purpose the following methods were used: spectrophotometry (protein carbonyls, glutathione and glutathione peroxidase assays), immunofluorescence (4‐hydroxy‐2‐nonenal localization), western blotting (immunodetection of carbonylated proteins). The results showed that compared to RBCs of healthy subjects, in obese Type 2 diabetics, ageing is associated with: (i) an increase in the concentration and expression of carbonylated proteins, a marker of oxidative stress; (ii) a decrease of both non‐enzymatic and enzymatic endogenous glutathione defenses; (iii) a severely disturbed oxidant/antioxidant balance when obesity was associated with hypertension. The simultaneous insults of high blood pressure, obesity, and diabetes conducted to the highest carbonyl strss, exposure of 4‐hydroxy‐2‐nonenal Michel adducts at the outer leaflet of RBCs plasmalemma, and the lowest glutathione antioxidant potential, particularly in elderly patients. These results can explain the gradual age‐dependent diminishment of the detoxification potenital of RBCs that at the old age can not overcome the deleterious effects of the high systemic oxidative stress.

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Section: Discussionmentioning

confidence: 71%

Effects of ageing on carbonyl stress and antioxidant defense in RBCs of obese Type 2 diabetic patients

Constantin¹,

Constantinescu²,

Dumitrescu³

et al. 2005

J Cellular Mol Med

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“…The enzyme catalyzes hydrolysis of the bond linking the glutamate and cysteine residues of extracellular glutathione and glutathione-S conjugates (15). GSAO is effectively a glutathione-S conjugate of aminophenylarsonous acid, so it is not surprising that it is a substrate for ␥GT.…”

Section: Discussionmentioning

confidence: 99%

“…␥GT-dependent metabolism of glutathione-S-hydroxy-2,3-trans-nonenal is associated with a considerable increase of cytotoxicity due to the release of cysteinyl-glycine-S-hydroxy-2,3-trans-nonenal (15). Also, ␥GT processing of mercuric glutathione conjugate to mercuric cysteinyl-glycine results in increased luminal uptake of the product in the proximal tubules of the kidney (19).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of the Tumor Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous Acid

Dilda

Ramsay

Corti

et al. 2008

Journal of Biological Chemistry

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4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) is a small, synthetic mitochondrial poison that targets angiogenic endothelial cells and is currently being tested in aPhase I/IIa clinical trial. The trivalent arsenical of GSAO reacts with and perturbs adenine nucleotide translocase of the inner mitochondrial membrane of endothelial cells, which leads to proliferation arrest. Three observations indicated that the ␥-glutamyl residue of GSAO is cleaved at the endothelial cell surface by ␥-glutamyl transpeptidase (␥GT). GSAO was found to be an efficient substrate for ␥GT, endothelial cell accumulation and antiproliferative activity of GSAO was blunted by a competitive substrate and an active site inhibitor of ␥GT, and the level of cell surface ␥GT correlated strongly with the sensitivity of cells to GSAO. Using transport inhibitors, it was revealed that the resulting metabolite of GSAO cleavage by ␥GT, 4-(N-(S-cysteinylglycylacetyl)amino) phenylarsonous acid (GCAO), was transported across the plasma membrane by an organic anion transporter. Furthermore, GCAO is likely processed by dipeptidases in the cytosol to 4-(N-(S-cysteinylacetyl)amino) phenylarsonous acid (CAO), and it is this metabolite that reacts with mitochondrial adenine nucleotide translocase. Taken together, our findings indicate that ␥GT processing of GSAO at the cell surface is the rate-limiting step in its antiangiogenic activity. This information can explain the kidney toxicity at high doses of GSAO noted in preclinical studies and will aid in the anticipation of potential side effects in humans and in the design of better antimitochondrial cancer drugs. GSAO2 is a mitochondrial poison that selectively perturbs angiogenic endothelial cells in vitro and in vivo (1-3). The tripeptide trivalent arsenical inactivates the mitochondrial inner membrane transporter, adenine nucleotide translocase (ANT), by cross-linking two of the three matrix facing cysteine thiols (1, 4). Proper functioning of ANT is essential for cell viability, so targeting this protein in angiogenic endothelial cells is a powerful means of blocking angiogenesis (5). A limitation of targeting specific angiogenic proteins is that they can often be circumvented by other proteins in the angiogenic process. GSAO is currently being tested in a Phase I/IIa clinical trial in cancer patients.ANT exchanges matrix ATP for intermembrane space ADP across the inner mitochondrial membrane and is a key component of the mitochondrial permeability transition pore (6, 7). Inactivation of ANT by GSAO causes an increase in superoxide levels, proliferation arrest, ATP depletion, mitochondrial depolarization, and apoptosis in endothelial cells. The strong selectivity of GSAO for proliferating endothelial cells is a consequence of the higher mitochondrial calcium levels in proliferating cells (1). ANT is a calcium receptor that undergoes a conformational change and a change in activity upon binding of calcium ions. GSAO binds to calcium-replete ANT but binds minimally in the absence of calcium io...

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“…Using HPLC-ESI-MS/MS (Ion trap mass spectrometer) to demonstrate the involvement of GGT in the GS-HNE metabolism (Enoiu et al, 2002), it has been identified for the first time cysteinylglycine-HNE (CysGly-HNE) as resulting metabolite in fibroblast cell lines on the basis of…”

Section: A Gsh and Histidine-containing Peptides As Hne Detoxifying mentioning

confidence: 99%

“…A more direct analytical approach (HPLC-ESI-MS/ MS) has been recently employed for the study of HNE conjugation with GSH in the rat in vivo (Boon et al, 1999), for the study of the g-glutamyl-transpeptidase(GTT)-dependent metabolic fate of GS-HNE conjugate in GTToverexpressing fibroblast cell lines (Enoiu et al, 2002) and for definition of the metabolic fate of HNE in epidermal cells (keratinocytes) Aldini et al, 2003). In the first study, the HPLC system (reversed-phase isocratic elution) was interfaced to a triple quadrupole tandem mass spectrometer that operated in the positive-ion mode only to identify in bile of i.v.…”

Section: A Gsh and Histidine-containing Peptides As Hne Detoxifying mentioning

confidence: 99%

Mass spectrometry for detection of 4‐hydroxy‐trans‐2‐nonenal (HNE) adducts with peptides and proteins

Carini

Aldini

Facino

2004

Mass Spectrometry Reviews

167

157

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Despite the great technical advancement of mass spectrometry, this technique has contributed in a limited way to the discovery and quantitation of specific/precocious markers linked to free radical-mediated diseases. Unsaturated aldehydes generated by free radical-induced lipid peroxidation of polyunsaturated fatty acids, and in particular 4-hydroxy-trans-2 nonenal (HNE), are involved in the onset and progression of many pathologies such as cardiovascular (atherosclerosis, long-term complications of diabetes) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of HNE are attributed to the capacity of HNE to react with the nucleophilic sites of proteins and peptides (other than nucleic acids), to form covalently modified biomolecules that can disrupt important cellular functions and induce mutations. By considering the emerging role of HNE in several human diseases, an unequivocal analytical approach as mass spectrometry to detect/elucidate the structure of protein-HNE adducts in biological matrices is strictly needed not only to understand the reaction mechanism of HNE, but also to gain a deeper insight into the pathological role of HNE. This with the aim to provide intermediate diagnostic biomarkers for human diseases. This review sheds focus on the "state-of-the-art" of mass spectrometric applications in the field of HNE-protein adducts characterization, starting from the fundamental early studies and discussing the different MS-based approaches that can provide detailed information on the mechanistic aspects of HNE-protein interaction. In the last decade, the increases in the accessible mass ranges of modern instruments and advances in ionization methods have made possible a fundamental improvement in the analysis of protein-HNE adducts by mass spectrometry, and in particular by matrix-assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) tandem mass spectrometry. The recent developments and uses of combined analytical approaches to detect and characterize the type/site of interaction have been highlighted, and several other aspects, including sample preparation methodologies, structure elucidation, and data analysis have also been considered.

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γ-Glutamyltranspeptidase-Dependent Metabolism of 4-Hydroxynonenal–Glutathione Conjugate

Cited by 31 publications

References 38 publications

Effects of ageing on carbonyl stress and antioxidant defense in RBCs of obese Type 2 diabetic patients

Effects of ageing on carbonyl stress and antioxidant defense in RBCs of obese Type 2 diabetic patients

Metabolism of the Tumor Angiogenesis Inhibitor 4-(N-(S-Glutathionylacetyl)amino)phenylarsonous Acid

Mass spectrometry for detection of 4‐hydroxy‐trans‐2‐nonenal (HNE) adducts with peptides and proteins

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