Gamma-tocopheryl quinone, not alpha-tocopheryl quinone, induces adaptive response through up-regulation of cellular glutathione and cysteine availability via activation of ATF4.

alpha-Tocopheryl quinone (alpha-TQ) and gamma-TQ are oxidized metabolites of the corresponding tocopherol (T) isoforms, which are vitamin E homologues. Unlike alpha-TQ, gamma-TQ functions as an arylating agent that reacts with nucleophiles such as reduced sulphydryl groups and it has unique biological properties such as high toxicity. Increasing evidence indicates that reactive oxygen species and other physiologically existing oxidative stimuli upregulate the antioxidant system, thereby triggering the adaptive response. The present study used PC12 cells and immature primary cortical cells to examine the possible adaptive cytoprotective effects of gamma-TQ against oxidative stress. Pre-treatment with gamma-TQ at sub-lethal concentrations resulted in cytoprotective effects against oxidative stress. gamma-TQ induced a significant increase in the cellular glutathione (GSH) levels while alpha-TQ did not. gamma-TQ did not induce any considerable change in the activity of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in GSH synthesis, whereas it increased the cellular GSH levels by facilitating the availability of cysteine through the induction of xCT, which is the core sub-unit of the x(c)(-) high-affinity cystine transporter system. An activating transcription factor 4 (ATF4)-small interfering RNA effectively attenuated the xCT mRNA level as well as the increase in cellular cysteine levels induced by gamma-TQ, while the NF-E2-related factor (Nrf2)-small interfering RNA treatment did not. Collectively, these findings indicate that gamma-TQ acts as a signal messenger to induce adaptive response through the upregulation of intracellular GSH synthesis via transcriptional activation of ATF4 in order to cope with the forthcoming oxidative insult.