Cadmium and α-lipoic acid activate similar de novo synthesis and recycling pathways for glutathione balance

Abstract

Glutathione (GSH) protects cells against oxidative stress. Redox modifiers induce GSH biosynthesis and recycling to maintain reduced environment inside cells. Cadmium (Cd²⁺) is a heavy metal that activates redox-sensitive transcriptional factors. The antioxidant α-lipoic acid (ALA) has shown to modulate GSH pathways. This study aimed to investigate de novo synthesis and recycling pathways for GSH balance by different Cd²⁺ concentrations and ALA in HepG2 cells. ALA activates Nrf2 pathway leading to GSH increment. Pre-treatment with 1μM Cd²⁺ or ALA produces tolerance to 5μM Cd²⁺ toxic effects. 5μM Cd²⁺ exposure significantly augmented nuclear Nrf2, GSH and GCLC, GCLM, HMOX1, TNFα and IL-6 mRNA expression but not GSR, however these upsurges were significantly abrogated by ALA or 1μM Cd²⁺ pre-treatments. Exposure to low Cd²⁺ concentration generate timely protective responses, similar to that elicited by ALA, maintaining a normal redox balance inside the cell due to GSH replenishment.

Keywords: -γ-GCL; Cadmium; GSR; Glutathione; Nrf2; α-Lipoic acid.