Mechanisms of interaction of acetaminophen metabolites in terms of hepatotoxicity
Current Issues in Pharmacy and Medical Sciences Vol. 26, No. 2, Pages 206-210
MILENA TOPOŁA*, MAGDALENA PODAWACZ, MARIOLA ŚLIWIŃSKA-MOSSOŃ,
WALDEMAR SAJEWICZ, HALINA MILNEROWICZ
Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
The most serious complication after ingestion of a toxic dose of acetaminophen is liver damage. The aim of study was to review the research on the biochemical and molecular mechanisms of acetaminophen hepatotoxicity. It was shown that effect of the acetaminophen metabolism is the production of N-acetyl-p-benzoquinone, which is formed by bioactivation with the participation of cytochrome P450 enzymes. The combination of N-acetyl-p-benzoquinone and proteins can cause a disruption in protein homeostasis in cell membrane and mitochondrion. It may interfere with cellular signal process. Small and chronic doses of acetaminophen lead to damage of the cell nucleus. These effects can explain the mechanism of hepatotoxicity. N- acetyl- pbenzoquinone can cause an increase in oxidative stress. Lipids peroxidation and proteins oxidation are the main factors, which lead to necrosis of hepatocytes. It was shown that N-acetyl-p-benzoquinone can cause a decrease in GSH level and SH groups. For this reason, N-acetyl-p-benzoquinone was recognized as a key factor of the acetaminophen hepatotoxicity.
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acetaminophen, covalent modification of proteins, cytochrome P-450, hepatotoxicity
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