Regeneration of glutathione by α-lipoic acid via Nrf2/ARE signaling pathway alleviates cadmium-induced HepG2 cell toxicity

• DOI: 10.1016/j.etap.2017.02.022
• Publication Date: 2017-02-28T07:30:57Z
• Authors: Jiayu Zhang; Xue Zhou; Wenbo Wu; Jiachun Wang; Hong Xie; Zhigang Wu
• Keywords: 0303 health sciences; Thioctic Acid; Cell Survival; NF-E2-Related Factor 2; Glutamate-Cysteine Ligase; Cell Culture Techniques; Hep G2 Cells; Glutathione; Antioxidant Response Elements; Antioxidants; Oxidative Stress; 03 medical and health sciences; Glutathione Reductase; Humans; Environmental Pollutants; Cadmium; Signal Transduction

Alpha-lipoic acid (α-LA) is an important antioxidant that is capable of regenerating other antioxidants, such as glutathione (GSH). However, the underlying molecular mechanism by which α-LA regenerates GSH remains poorly understood. The current study aimed to investigate whether α-LA regenerates GSH by activation of Nrf2 to alleviate cadmium-induced cytotoxicity in HepG2 cells. In the present study, we found that cadmium induced cell death by depletion of GSH through inactivation of Nrf2. Addition of α-LA to cadmium-treated cells reactivated Nrf2 and regenerated GSH through elevating the Nrf2-downstream genes γ-glutamate-cysteine ligase (γ-GCL) and GR, both of which are key enzymes for GSH synthesis. However, blocking Nrf2 with brusatol in the cells co-treated with α-LA and cadmium reduced the mRNA and the protein levels of γ-GCL and GR, thus suppressed GSH regeneration by α-LA. Our results indicated that α-LA activated Nrf2 signaling pathway, which upregulated the transcription of the enzymes for GSH synthesis and therefore GSH contents to alleviate cadmium-induced cytotoxicity in HepG2 cells.