The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis

Abstract

Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. ROLE OF OXIDATIVE STRESS IN PARACETAMOL-INDUCED LIVER INJURY: The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol-induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils. Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. ROLE OF MITOCHONDRIA IN PARACETAMOL-INDUCED OXIDATIVE STRESS: The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mitochondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonucleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. ROLE OF KUPFFER CELLS IN PARACETAMOL-INDUCED LIVER INJURY: Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. ROLE OF NEUTROPHILS IN PARACETAMOL-INDUCED LIVER INJURY: Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. ROLE OF PEROXYNITRITE IN PARACETAMOL-INDUCED OXIDATIVE STRESS: Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species.