Abstract
The alpha class glutathione s-transferase (GST) isozyme GSTA4-4 (EC2.5.1.18) exhibits high catalytic efficiency to-wards 4-hydroxynon-2-enal (4-HNE), a major end product of oxidative stress induced lipid peroxidation. Exposure of cells and tissues to heat, radiation, and chemicals has been shown to induce oxidative stress resulting in elevated concentrations of 4-HNE that can be detrimental to cell survival. Alternatively, at physiological levels 4-HNE acts as a signaling molecule conveying the occurrence of oxidative events initiating the activation of adaptive pathways. To examine the impact of oxidative/electrophilic stress in a model with impaired 4-HNE metabolizing capability, we disrupted the Gsta4 gene that encodes GSTA4-4 in mice. The effect of electrophile and oxidants on embryonic fibroblasts (MEF) isolated from wild type (WT) and Gsta4 null mice were examined. Results indicate that in the absence of GSTA4-4, oxidant-induced toxicity is potentiated and correlates with elevated accumulation of 4-HNE adducts and DNA damage. Treatment of Gsta4 null MEF with 1,1,4-tris(acetyloxy)-2(E)-nonene [4-HNE(Ac)3], a pro-drug form of 4-HNE, resulted in the activation and phosphorylation of the c-jun-N-terminal kinase (JNK), extracellular-signal-regulated kinases (ERK 1/2) and p38 mitogen activated protein kinases (p38 MAPK) accompanied by enhanced cleavage of caspase-3. Interestingly, when recombinant mammalian or invertebrate GSTs were delivered to Gsta4 null MEF, activation of stress-related kinases in 4-HNE(Ac)3 treated Gsta4 null MEF were inversely correlated with the catalytic efficiency of delivered GSTs towards 4-HNE. Our data suggest that GSTA4-4 plays a major role in protecting cells from the toxic effects of oxidant chemicals by attenuating the accumulation of 4-HNE.
Highlights
Lipid aldehydes generated during lipid peroxidation (LPO) are highly reactive species capable of electrophilic attack on DNA and proteins [1,2,3,4]. 4-HNE, one of the major end products of LPO, causes cytotoxicity and genotoxicity by inducing necrosis and pro-apoptotic signaling through multiple pathways at supraphysiological concentrations [5,6,7]. 4-HNE is involved in regulation of gene expression and cell cycle signaling in a concentration dependent manner [8,9,10,11]
Deletion of Gsta4 was predicted to potentiate sensitivity towards 4HNE, and we examined sensitivity of Gsta4 null MEF towards other oxidants, H2O2 and paraquat known to be metabolized by catalase and superoxide dismutases (SOD)
To distinguish between the various modes of glutathione s-transferase (GST) action, we directly introduce mGSTA4-4, the phylogenetically distant Drosophila DmGSTD1-1 [27], and hGSTA1-1 into Gsta4 null cells. mGSTA4-4 and, to a lesser extent, consistent with its lower activity, DmGSTD1-1 were able to abrogate the activation of p38 MAPK and jun-N-terminal kinase (JNK) (Figure 7) by 4-HNE(Ac)3, whereas hGSTA1-1 had no effect
Summary
Lipid aldehydes generated during lipid peroxidation (LPO) are highly reactive species capable of electrophilic attack on DNA and proteins [1,2,3,4]. 4-HNE, one of the major end products of LPO, causes cytotoxicity and genotoxicity by inducing necrosis and pro-apoptotic signaling through multiple pathways at supraphysiological concentrations [5,6,7]. 4-HNE is involved in regulation of gene expression and cell cycle signaling in a concentration dependent manner [8,9,10,11]. Lipid aldehydes generated during lipid peroxidation (LPO) are highly reactive species capable of electrophilic attack on DNA and proteins [1,2,3,4]. 4-HNE, one of the major end products of LPO, causes cytotoxicity and genotoxicity by inducing necrosis and pro-apoptotic signaling through multiple pathways at supraphysiological concentrations [5,6,7]. 4-HNE is involved in regulation of gene expression and cell cycle signaling in a concentration dependent manner [8,9,10,11]. We and others [12,13] have shown that 4-HNE causes activation and phosphorylation of the c-jun-N-terminal kinase (JNK) and p38 mitogen activated
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