Glutathione Depletion and Mitochondrial Dysfunction in Paracetamol-Induced Hepatic Damage

Abstract

Paracetamol-induced hepatic injury is a widely studied model of drug-related liver toxicity in which depletion of glutathione and impairment of mitochondrial function are key pathogenic events. During paracetamol overdose, excessive formation of the reactive metabolite N-acetyl-p-benzoquinone imine overwhelms hepatic detoxification capacity and rapidly consumes intracellular glutathione. Loss of this critical antioxidant defense leads to enhanced oxidative and nitrosative stress within hepatocytes. The resulting redox imbalance directly affects mitochondrial integrity by disrupting the electron transport system, reducing ATP synthesis, and altering mitochondrial membrane potential. These mitochondrial alterations promote permeability transition, calcium dysregulation, and activation of cell death pathways, ultimately leading to hepatocellular necrosis. Mitochondrial dysfunction further exacerbates liver injury by amplifying oxidative stress and inflammatory signaling. Experimental studies in rats demonstrate that maintenance of glutathione levels and preservation of mitochondrial function markedly reduce the severity of paracetamol-induced liver damage. Accordingly, biochemical assessment of glutathione status, mitochondrial enzymes, and energy metabolism has become central to mechanistic and hepatoprotective investigations. Overall, understanding the interplay between glutathione depletion and mitochondrial dysfunction provides valuable insight into paracetamol-induced hepatotoxicity and supports the development of targeted hepatoprotective interventions.