Introduction. 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 mito?chondrial dysfunction with adenosine triphosphate
depletion, increase mitochondrial permeability transition, deoxyribonu?cleic
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. Conclusion. 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.
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