Review ArticleRegulatory roles of glutathione-S-transferases and 4-hydroxynonenal in stress-mediated signaling and toxicity
Graphical abstract
Introduction
Since the seminal discovery of 4-hydroxy-trans 2-nonenal (HNE) as an end product of lipid peroxidation by Esterbauer's group [1], [2], HNE has attracted a great deal of attention because of its potential toxicity as well as its physiological roles, particularly in cell cycle signaling [1], [3], [4], [5], [6], [7], [8]. HNE is the major end-product from the peroxidation of n-6-polyunsaturated fatty acids and is sufficiently stable. Due to its carbonyl group at position 1 and the reactive 2,3-unsaturated double bond that is rendered more reactive by the presence of a hydroxyl group at the position 4, HNE is believed to impart its toxicity through interactions with nucleophilic groups of cellular components including proteins, nucleic acids and phospholipids [9], [10]. Initially thought to be merely a “toxic end-product”, in recent years HNE has acquired reputation as a major “second messenger” that affects cell cycle signaling in a concentration-dependent manner and has been one of the most extensively studied molecule during the past three decades with more than four thousand published studies on its multifarious effects on cellular processes.
Glutathione S-transferases (GSTs) use HNE as a substrate [11] and it has been shown that these enzymes function as the major determinants of cellular levels of HNE by attenuating its formation during lipid peroxidation and also through its metabolism via conjugation to glutathione (GSH) [11], [12], [13], [14]. Recent studies by us and others provide credible evidence that by modulating the intracellular levels of HNE, GSTs play a major role in the regulation of oxidative stress–induced toxicity and signaling [1], [3], [4], [5], [6], [7], [8]. In this article, the role of HNE in oxidative stress-induced signaling and its regulation by GSTs is reviewed against the back drop of general mechanism of stress signaling.
Section snippets
HNE and signaling
Whereas many of the initial studies on the role of HNE in signaling, e.g. stimulation of adenylate cyclase [15], phospholipase C [16], [17], effects on chemo-taxis [18], and DNA synthesis [19] did not attract much attention, in recent years major roles of HNE in the cell cycle signaling including the induction of apoptosis as well as the activation of many cellular protective mechanisms in response to stress have been widely recognized and it is now considered as one of the major signaling
Physiological significance of maintaining HNE homeostasis
Earlier studies have shown that low levels of exogenously added HNE in the medium promote proliferation of certain cell types while at relatively higher concentrations in the medium, HNE mediates signaling for various cellular processes, including apoptosis [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39]. It is noteworthy that such hormetic effect of H2O2 has also been observed in studies where low levels of H2O2 promote DNA and protein
GSTs and HNE metabolism
Generation of HNE from lipid peroxidation of n-6-polyunsaturated fatty acids is an uncontrollable process depending on the ever-changing levels of endogenous ROS as well as the environmental factors such as exposure to oxidants, radiation, and drugs/xenobiotics that cause oxidative stress. Therefore, the major burden of maintaining cellular HNE homeostasis must be on enzymes that metabolize HNE and eliminate the resultant metabolites from the cells. HNE being sufficiently electrophilic can
Regulation of HNE-mediated signaling by GSTs
Voluminous literature is available demonstrating involvement of HNE in signaling process and many of these studies have been covered in several excellent reviews [3], [4], [5], [6], [7], [8]. Majority of these studies focus on the effect of HNE on a specific target using a single cell line. Studies on the effect of HNE depletion using several human cell lines of different tissue origin as well as a regulatory role of GSTs in the various processes are worth noting here because these studies
Role of HNE and GSTs in the regulation of cell cycle arrest and DNA repair
HNE also causes cell cycle arrest through mechanisms similar to those known for DNA damage-induced G1/G0 or G2/M cell cycle arrest and seems to be involved in the mechanisms of cell cycle arrest during DNA-damage [37], [101], [102]. As discussed above, HNE can simultaneously activate both pro- and anti-apoptotic singling pathways and that these are regulated by GSTA4-4 [8]. Our recent studies show that HNE induces G2/M phase cell cycle arrest during which ataxia telangiectasia mutated and Rad3
Future perspectives
The available evidence strongly indicate that GSTs regulate HNE-mediated toxicity and signaling by either attenuating HNE formation or through its conjugate GS-HNE formation that is eventually eliminated from cells through RLIP76-mediated transport. As detailed above, the Alpha class of GST enzymes GSTA1-1 and GSTA2-2 that prevent HNE formation and GSTA4-4 that catalyze the conjugation of HNE to GSH play an important role in this process. However, the role of other GST isozymes particularly GST
Acknowledgments
Supported by funding from NIH, United States Grants CA129383 and DK104786.
References (118)
- et al.
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Free Radic. Biol. Med.
(1991) - et al.
Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids
Biochim. Biophys. Acta
(1980) - et al.
Lipid oxidation products in cell signaling
Free Radic. Biol. Med.
(2000) - et al.
Regulation of 4-hydroxynonenal-mediated signaling by glutathione S-transferases
Free Radic. Biol. Med.
(2004) - et al.
Glutathione dependent metabolism and detoxification of 4-hydroxy-2-nonenal
Free Radic. Biol. Med.
(1991) Basic aspects of the biochemical reactivity of 4-hydroxynonenal
Mol. Asp. Med.
(2003)- et al.
4-hydroxyalk-2-enals are substrates for glutathione transferase
FEBS Lett.
(1985) - et al.
Role of alpha class glutathione S-transferases as antioxidant enzymes in rodent tissues
Toxicol. Appl. Pharmacol.
(2002) - et al.
Antioxidant role of glutathione S-transferases: 4-hydroxynonenal, a key molecule in stress-mediated signaling
Toxicol. Appl. Pharmacol.
(2015) - et al.
Contribution of 4-hydroxy-2,3-trans-nonenal to the reduction of beta-adrenoceptor function in the heart by oxidative stress
Life Sci.
(1989)
Reversible inhibition of DNA and protein synthesis by cumene hydroperoxide and 4-hydroxy-nonenal
Mech. Ageing Dev.
Vascular smooth muscle cell activation and growth by 4-hydroxynonenal
Life Sci.
Induction of cell cycle arrest and DNA damage by the HDAC inhibitor panobinostat (LBH589) and the lipid peroxidation end product 4-hydroxynonenal in prostate cancer cells
Free Radic. Biol. Med.
Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death
Free Radic. Biol. Med.
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
J. Biol. Chem.
Role of glutathione S-transferases in protection against lipid peroxidation. Overexpression of hGSTA2-2 in K562 cells protects against hydrogen peroxide-induced apoptosis and inhibits JNK and caspase 3 activation
J. Biol. Chem.
Role of 4-hydroxynonenal in stress-mediated apoptosis signaling
Mol. Asp. Med.
4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway
J. Biol. Chem.
4-Hydroxynonenal as a bioactive marker of pathophysiological processes
Mol. Asp. Med.
Low doses of reactive oxygen species protect endothelial cells from apoptosis by increasing thioredoxin-1 expression
FEBS Lett.
NR8383 alveolar macrophage toxic growth arrest by hydrogen peroxide is associated with induction of growth-arrest and DNA damage-inducible genes GADD45 and GADD153
Toxicol. Appl. Pharmacol.
Effects of mGST A4 transfection on 4-hydroxynonenal-mediated apoptosis and differentiation of K562 human erythroleukemia cells
Arch. Biochem. Biophys.
The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase
Arch. Biochem. Biophys.
Glutathione-S-transferase family of enzymes
Mutat. Res.
Estimation of genomic complexity, heterologous expression, and enzymatic characterization of mouse glutathione S-transferase mGSTA4-4 (GST 5.7)
J. Biol. Chem.
A subgroup of class alpha glutathione S-transferases. Cloning of cDNA for mouse lung glutathione S-transferase GST 5.7
FEBS Lett.
Several closely related glutathione S-transferase isozymes catalyzing conjugation of 4-hydroxynonenal are differentially expressed in human tissues
Arch. Biochem. Biophys.
A novel glutathione S-transferase isozyme similar to GST 8-8 of rat and mGSTA4-4 (GST 5.7) of mouse is selectively expressed in human tissues
Biochim. Biophys. Acta
Subunit structure of human and rat glutathione S-transferases
Comp. Biochem. Physiol. B
RLIP76 in defense of radiation poisoning
Int. J. Radiat. Oncol. Biol. Phys.
Lipid peroxidation product, 4-hydroxynonenal and its conjugate with GSH are excellent substrates of bovine lens aldose reductase
Biochem. Biophys. Res. Commun.
In vivo involvement of cytochrome P450 4A family in the oxidative metabolism of the lipid peroxidation product trans-4-hydroxy-2-nonenal, using PPARalpha-deficient mice
J. Lipid Res.
Cytochromes P450 catalyze oxidation of alpha,beta-unsaturated aldehydes
Arch. Biochem. Biophys.
Metabolism of 4-hydroxynonenal, a cytotoxic product of lipid peroxidation, in rat precision-cut liver slices
Toxicol. Lett.
Aldehyde dehydrogenases and cancer stem cells
Cancer Lett.
Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress
Free Radic. Biol. Med.
Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE): role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth
J. Biol. Chem.
Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages
J. Biol. Chem.
The role of human glutathione S-transferases hGSTA1-1 and hGSTA2-2 in protection against oxidative stress
Arch. Biochem. Biophys.
Membrane association of glutathione S-transferase mGSTA4-4, an enzyme that metabolizes lipid peroxidation products
J. Biol. Chem.
Glutathione S-transferases as antioxidant enzymes: small cell lung cancer (H69) cells transfected with hGSTA1 resist doxorubicin-induced apoptosis
Arch. Biochem. Biophys.
Cells preconditioned with mild, transient UVA irradiation acquire resistance to oxidative stress and UVA-induced apoptosis: role of 4-hydroxynonenal in UVA-mediated signaling for apoptosis
J. Biol. Chem.
Depletion of 4-hydroxynonenal in hGSTA4-transfected HLE B-3 cells results in profound changes in gene expression
Biochem. Biophys. Res. Commun.
Role of 4-hydroxynonenal in chemopreventive activities of sulforaphane
Free Radic. Biol. Med.
HNE-signaling pathways leading to its elimination
Mol. Asp. Med.
Role of 4-hydroxynonenal in epidermal growth factor receptor-mediated signaling in retinal pigment epithelial cells
Exp. Eye Res.
Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: generation and analysis of mGSTA4 null mouse
Toxicol. Appl. Pharmacol.
Relationship of electrophilic stress to aging
Free Radic. Biol. Med.
4-hydroxynonenal and cell signaling
Free Radic. Res.
Role of 4-hydroxynonenal and its metabolites in signaling
Redox Rep.
Cited by (42)
Glutathione and glutathione-dependent enzymes: From biochemistry to gerontology and successful aging
2023, Ageing Research ReviewsIntracellular second messengers mediate stress inducible hormesis and Programmed Cell Death: A review
2019, Biochimica et Biophysica Acta - Molecular Cell ResearchCitation Excerpt :For example, lipid peroxidation products of polyunsaturated fatty acids (PUFAs) such as 4-hydroxy-2-nonenal (4HNE) can function as intracellular second messengers that can induce apoptotic as well as hormetic responses [406–408]. A variety of different conditions that can induce oxidative stresses leading to pre-conditioning or apoptosis including UV radiation, aging, xenobiotics and drugs have been shown to lead to increases in 4HNE [408–410]. ROS damaged or denatured proteins can also act as an intracellular second messenger in part by binding to and activating a variety of heat shock proteins [404,411].
Na<sup>+</sup>/K<sup>+</sup>-ATPase, acetylcholinesterase and glutathione S-transferase activities as new markers of postmortem interval in Swiss mice
2019, Legal MedicineCitation Excerpt :GSTs have primarily been thought to be xenobiotic metabolizing enzymes that protect cells from toxic drugs and environmental electrophiles. However, in last three decades, these enzymes have emerged as the regulators of oxidative stress-induced signaling and toxicity [61–65]. Although promising results have been obtained here, it is important to note that the standard experimental conditions (temperature controlled, fed animals, death induced by isoflurane inhalation, and male adult Swiss mice) are among the possible limitations of this study.