Aldo–keto reductase 7A5 (AKR7A5) attenuates oxidative stress and reactive aldehyde toxicity in V79-4 cells

Li, Dan and Ellis, Elizabeth M. (2014) Aldo–keto reductase 7A5 (AKR7A5) attenuates oxidative stress and reactive aldehyde toxicity in V79-4 cells. Toxicology in Vitro, 28 (4). pp. 707-714. ISSN 0887-2333 (https://doi.org/10.1016/j.tiv.2014.02.010)

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Abstract

Aldo-keto reductase (AKR) enzymes are critical in the detoxification of endogenous and exogenous aldehydes. In previous studies, we have shown that AKR7A5 enzyme is catalytically active towards aldehydes arising from lipid peroxidation (LPO) and that it can significantly protect against 4-hydroxynonenal-induced apoptosis, suggesting a protective role against the consequences of oxidative stress. The aim of this study was to elucidate the cytoprotective effect of AKR7A5 against oxidative stress using a transgenic mammalian cell line expressing AKR7A5. Results show that expression of AKR7A5 in V79-4 cells provides significant protection against the cytotoxicity of H2O2 and menadione, with its expression altering the IC50 of H2O2 from 1.1 to 2.3mM and the IC50 of menadione from 8.6 to 9.6μM, thus providing direct evidence for its anti-oxidant activity. Cells expressing AKR7A5 were also found to be more resistant to several LPO-derived aldehydes - trans-2-nonenal, hexanal and methylglyoxal. In addition the ability of AKR7A5 to enable the cells to cope with ROS accumulation and glutathione depletion was assessed. V79-4 cells overexpressing AKR7A5 were able to lower cellular ROS levels following treatment with H2O2 and menadione. AKR7A5 was also able to maintain cellular glutathione homeostasis in the presence of H2O2 and menadione. These findings indicate the importance of AKR7A5 in protecting cells from the damaging effects of oxidative stress, and that this cytoprotective function is carried out through multiple pathways.

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