title: Antioxidant role of glutathione S-transferases: 4-Hydroxynonenal, a key molecule in stress-mediated signaling.
abstract: 4-Hydroxy-2-trans-nonenal (4HNE), one of the major end products of lipid peroxidation (LPO), has been shown to induce apoptosis in a variety of cell lines. It appears to modulate signaling processes in more than one way because it has been suggested to have a role in signaling for differentiation and proliferation. It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione-peroxidase activity and that these enzymes can also detoxify LPO end-products such as 4HNE. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that LPO products, particularly hydroperoxides and 4HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the alpha-class GSTs through the regulation of the intracellular concentrations of 4HNE. We demonstrate that 4HNE induced apoptosis in various cell lines is accompanied with c-Jun-N-terminal kinase (JNK) and caspase-3 activation. Cells exposed to mild, transient heat or oxidative stress acquire the capacity to exclude intracellular 4HNE at a faster rate by inducing GSTA4-4 which conjugates 4HNE to glutathione (GSH), and RLIP76 which mediates the ATP-dependent transport of the GSH-conjugate of 4HNE (GS-HNE). The balance between formation and exclusion promotes different cellular processes - higher concentrations of 4HNE promote apoptosis; whereas, lower concentrations promote proliferation. In this article, we provide a brief summary of the cellular effects of 4HNE, followed by a review of its GST-catalyzed detoxification, with an emphasis on the structural attributes that play an important role in the interactions with alpha-class GSTA4-4. Taken together, 4HNE is a key signaling molecule and that GSTs being determinants of its intracellular concentrations, can regulate stress-mediated signaling, are reviewed in this article.
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, United States. Electronic address: ssinghal@coh.org.
authors.forename: Sharad S
authors.initials: SS
authors.lastname: Singhal
authors.affiliation: Pharmacology and Toxicology, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, United States.
authors.forename: Sharda P
authors.initials: SP
authors.lastname: Singh
authors.affiliation: University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States.
authors.forename: Preeti
authors.initials: P
authors.lastname: Singhal
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, United States.
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.affiliation: Department of Diabetes & Metabolic Diseases Research, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, United States.
authors.forename: Jyotsana
authors.initials: J
authors.lastname: Singhal
authors.affiliation: Department of Medical Oncology, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center, Duarte, CA 91010, United States.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Awasthi
mesh_terms: D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D007527:Isoenzymes; D005982:Glutathione Transferase; C119995:glutathione S-transferase alpha; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal; Glutathione S-transferase; Glutathione-conjugates; Lipid peroxidation; RLIP76