Metal-Induced Oxidative Stress and Antioxidant Defense: A Review of the Current State of Knowledge and Therapeutic Implications

Research Article

Abstract

Heavy metals such as lead, cadmium, mercury, and arsenic are persistent environmental and occupational toxicants that induce cellular damage primarily through oxidative stress. By generating reactive oxygen species (ROS) and disrupting the cellular redox balance, these metals impair mitochondrial function, DNA integrity, and protein structure. In response, organisms activate antioxidant defense systems involving enzymatic and non-enzymatic components to neutralize ROS and restore homeostasis. Chronic metal exposure overwhelms these defenses, contributing to neurodegenerative, cardiovascular, and renal diseases. This review examines the mechanisms of metal-induced oxidative stress, endogenous antioxidant responses, and emerging therapeutic strategies aimed at mitigating metal toxicity. Metal ions catalyze Fenton-like reactions and deplete glutathione, leading to elevated ROS levels and lipid peroxidation. Lead and cadmium primarily target the sulfhydryl groups of antioxidant enzymes, inhibiting superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Mercury binds directly to mitochondrial complexes, increasing superoxide production and triggering apoptosis. Arsenic induces oxidative stress via the activation of NADPH oxidase and disruption of cellular signaling pathways. Transcriptomic studies reveal upregulation of nuclear factor erythroid 2–related factor 2 (Nrf2) as a key adaptive response that enhances expression of antioxidant and detoxification genes. Exogenous antioxidants such as vitamin C, vitamin E, and N-acetylcysteine have shown protective effects in preclinical models by scavenging ROS and chelating metals. Phytochemicals including curcumin, quercetin, and resveratrol demonstrate dual roles as metal chelators and Nrf2 activators. Chelation therapy with EDTA and DMSA remains the clinical standard for acute metal poisoning but carries risks of renal toxicity and essential mineral depletion. Recent nanotechnology-based approaches using selenium nanoparticles and metal-organic frameworks show enhanced biocompatibility and targeted delivery for oxidative stress mitigation. Metal-induced oxidative stress is a central mechanism underlying metal toxicity and associated chronic diseases. While endogenous antioxidant systems provide initial protection, prolonged exposure necessitates therapeutic intervention. Current strategies combining chelation with antioxidant supplementation show promise but require optimization for safety and efficacy. Future research should focus on personalized antioxidant therapies, biomarker development for early oxidative damage, and environmentally sustainable chelating agents.