Glutathione Conjugation of 4-Hydroxy-trans-2,3-nonenal in the Rat in Vivo, the Isolated Perfused Liver and Erythrocytes

Boon, P. J. M.; Marinho, H. Susana; Oosting, Roelof; Mulder, Gerard J.

doi:10.1006/taap.1999.8742

Cited by 49 publications

(44 citation statements)

References 32 publications

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“…4A). This was consistent with previous studies showing multiple peaks for GS-HNE due to its diastereoisomers (26). The conjugation of 4-HNE to GSH results in two chiral carbon atoms, and the subsequent ring closure of GS-HNE yields another chiral carbon, giving rise to the possibility of up to a maximum of eight diastereoisomers of GS-HNE (26).…”

Section: Hgst58 and Rlip76 Induction Suppresses Jnk Activationsupporting

confidence: 92%

Accelerated Metabolism and Exclusion of 4-Hydroxynonenal through Induction of RLIP76 and hGST5.8 Is an Early Adaptive Response of Cells to Heat and Oxidative Stress

Cheng¹,

Sharma²,

Yang³

et al. 2001

Journal of Biological Chemistry

174

238

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To explore the role of lipid peroxidation (LPO) products in the initial phase of stress mediated signaling, we studied the effect of mild, transient oxidative or heat stress on parameters that regulate the cellular concentration of 4-hydroxynonenal (4-HNE). When K562 cells were exposed to mild heat shock (42°C, 30 min) or oxidative stress (50 M H 2 O 2 , 20 min) and allowed to recover for 2 h, there was a severalfold induction of hGST5.8, which catalyzes the formation of glutathione-4-HNE conjugate (GS-HNE), and RLIP76, which mediates the transport of GS-HNE from cells (Awasthi, S., Cheng, J., Singhal, S. S., Saini, M. K., Pandya, U., Pikula, S., Bandorowicz-Pikula, J., Singh, S. V., Zimniak, P., and Awasthi, Y. C. (2000) Biochemistry 39, 9327-9334). Enhanced LPO was observed in stressed cells, but the major antioxidant enzymes and HSP70 remained unaffected. The stressed cells showed higher GS-HNEconjugating activity and increased efflux of GS-HNE. Stress-pre-conditioned cells with induced hGST5.8 and RLIP76 acquired resistance to 4-HNE and H 2 O 2 -mediated apoptosis by suppressing a sustained activation of c-Jun N-terminal kinase and caspase 3. The protective effect of stress pre-conditioning against apoptosis was abrogated by coating the cells with anti-RLIP76 IgG, which inhibited the efflux of GS-HNE from cells, indicating that the cells acquired resistance to apoptosis by metabolizing and excluding 4-HNE at a higher rate. Induction of hGST5.8 and RLIP76 by mild, transient stress and the resulting resistance of stress-pre-conditioned cells to apoptosis appears to be a general phenomenon since it was not limited to K562 cells but was also evident in lung cancer cells, H-69, H-226, human leukemia cells, HL-60, and human retinal pigmented epithelial cells. These results strongly suggest a role of LPO products, particularly 4-HNE, in the initial phase of stress mediated signaling.

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Section: Hgst58 and Rlip76 Induction Suppresses Jnk Activationsupporting

confidence: 92%

Accelerated Metabolism and Exclusion of 4-Hydroxynonenal through Induction of RLIP76 and hGST5.8 Is an Early Adaptive Response of Cells to Heat and Oxidative Stress

Cheng¹,

Sharma²,

Yang³

et al. 2001

Journal of Biological Chemistry

174

238

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“…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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“…Furthermore, Hiratsuka et al (32) demonstrated that the S-HNE enantiomer irreversibly inactivated rabbit glyceraldehyde-3-phosphate dehydrogenase at a greater rate than R-HNE. They also found a stereoselective consumption of substrate by rat GSTA4-4 in the order of S-HNE Ͼ racemic HNE Ͼ R-HNE (33), whereas a separate study by Boon et al (28) speculated that product stereoselectivity on behalf of GSTs is one potential explanation for the unequal distribution of GSHNE diastereomers observed in rat liver cytosol. Chirality has also been implicated as an important factor in other enzymes, such as aldehyde-dehydrogenase and aldo-keto reductases, that can also contribute to HNE metabolism and subsequent biotransformations of GSHNE (34 -36).…”

mentioning

confidence: 94%

“…Conjugation to GSH has been identified as the primary route of HNE detoxification followed by oxidative/reductive modifications and, ultimately, mercapturic acid formation (25)(26)(27)(28). Although HNE can spontaneously react with GSH to form a conjugate (GSHNE), GSTs have been found to significantly enhance the rate of this 1,4-addition reaction (see Fig.…”

mentioning

confidence: 99%

The Stereochemical Course of 4-Hydroxy-2-nonenal Metabolism by Glutathione S-Transferases

Balogh

Roberts

Shireman

et al. 2008

Journal of Biological Chemistry

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4-Hydroxy-2-nonenal (HNE) is a toxic aldehyde generated during lipid peroxidation and has been implicated in a variety of pathological states associated with oxidative stress. Glutathione S-transferase (GST) A4-4 is recognized as one of the predominant enzymes responsible for the metabolism of HNE. However, substrate and product stereoselectivity remain to be fully explored. The results from a product formation assay indicate that hGSTA4-4 exhibits a modest preference for the biotransformation of S-HNE in the presence of both enantiomers. Liquid chromatography mass spectrometry analyses using the racemic and enantioisomeric HNE substrates explicitly demonstrate that hGSTA4-4 conjugates glutathione to both HNE enantiomers in a completely stereoselective manner that is not maintained in the spontaneous reaction. Compared with other hGST isoforms, hGSTA4-4 shows the highest degree of stereoselectivity. NMR experiments in combination with simulated annealing structure determinations enabled the determination of stereochemical configurations for the GSHNE diastereomers and are consistent with an hGSTA4-4-catalyzed nucleophilic attack that produces only the S-configuration at the site of conjugation, regardless of substrate chirality. In total these results indicate that hGSTA4-4 exhibits an intriguing combination of low substrate stereoselectivity with strict product stereoselectivity. This behavior allows for the detoxification of both HNE enantiomers while generating only a select set of GSHNE diastereomers with potential stereochemical implications concerning their effects and fates in biological tissues.Stereochemical configuration is a fundamental aspect of molecular structure, and the functional consequences of dynamic stereochemistry in biology are well established (1-6). Substrate stereoselectivity may occur in enzyme-mediated catalysis by virtue of the innate asymmetry of the active site. Product stereoselectivity may also arise when new chiral centers are introduced during an enzymatic reaction, because enzymes may specifically stabilize only one of the possible transition states for a given reaction. Stereoselective metabolism of both xenobiotic and endogenous molecules is a well recognized phenomenon that reflects this underlying chiral recognition process. To the extent that stereochemically distinct substrates and products have different biological effects, it is essential to define the stereochemical course of enzymatic reactions.Among the molecules generated endogenously from the degradation of polyunsaturated fatty acids during lipid peroxidation, the unsaturated aldehyde 4-hydroxy-2-nonenal (HNE) 2 has been implicated in a variety of pathological states associated with the deleterious consequences of oxidative stress, including atherosclerosis, diabetes, Alzheimer disease, and Parkinson disease (7-11). HNE has been proposed to exert a number of toxicological effects via its electrophilic ␣,␤-unsaturated carbonyl moiety that can react through additions with nucleophiles such as cysteine, histidine, a...

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Glutathione Conjugation of 4-Hydroxy-trans-2,3-nonenal in the Rat in Vivo, the Isolated Perfused Liver and Erythrocytes

Cited by 49 publications

References 32 publications

Accelerated Metabolism and Exclusion of 4-Hydroxynonenal through Induction of RLIP76 and hGST5.8 Is an Early Adaptive Response of Cells to Heat and Oxidative Stress

Accelerated Metabolism and Exclusion of 4-Hydroxynonenal through Induction of RLIP76 and hGST5.8 Is an Early Adaptive Response of Cells to Heat and Oxidative Stress

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

The Stereochemical Course of 4-Hydroxy-2-nonenal Metabolism by Glutathione S-Transferases

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