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The aim of this study was to investigate the involvement of membrane-bound microsomal glutathione transferase 1 (MGST1) in cellular resistance against oxidative stress as well as its mechanism of protection. MGST1 is ubiquitously expressed and predominantly located in the endoplasmic reticulum and outer mitochondrial membrane. Utilizing MCF7 cells overexpressing MGST1 we show significant protection against agents that are known to induce lipid peroxidation (e.g., cumene hydroperoxide and
tert-butylhydroperoxide) and an end-product of lipid peroxidation (e.g., 4-hydroxy-2-nonenal). Furthermore, our results demonstrate that MGST1 protection can be enhanced by vitamin E when toxicity depends on oxidative stress, but not when direct alkylation is the dominant mechanism. Mitochondria in MGST1-overexpressing cells were shown to be protected from oxidative insult as measured by calcium loading capacity and respiration. MGST1 induces cellular resistance against cisplatin. Here we used vitamin E to elucidate whether oxidative stress caused by cisplatin is significant for cell toxicity. The results indicate that oxidative stress and induction of lipid peroxidation are not the most prominent toxic mechanism of cisplatin in our cell system. We thus conclude that MGST1 protects cells (and mitochondria) by both conjugation and glutathione peroxidase functions. A new protective mechanism against cisplatin is also indicated.