In-source formation of N-acetyl-p-benzoquinone imine (NAPQI), the putatively toxic acetaminophen (paracetamol) metabolite, after derivatization with pentafluorobenzyl bromide and GC–ECNICI-MS analysis

Tsikas, Dimitrios; Trettin, Arne; Zörner, A.; Gutzki, Frank‐Mathias

doi:10.1016/j.jchromb.2011.01.025

Cited by 13 publications

(5 citation statements)

References 30 publications

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“…It is well known that a large dose of acetaminophen causes hepatic GSH depletion because NAPQI, a reactive toxic metabolite of acetaminophen, is rapidly coupled with GSH in the presence of GST. 16,17 Therefore, the hepatotoxicity of acetaminophen depends on a balance between the rate of reactive metabolite NAPQI formation and regeneration of the GSH. 18,19 The remaining part of NAPQI may combine with cellular macromolecules by covalent binding and cause lipid peroxidation by reactive oxygen species formation, and nally lead to liver injury.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity

et al. 2013

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Apigenin, a natural plant flavone, has many beneficial effects, but there is no report about treatment of acetaminophen-induced liver injury. Our aim was to examine the protective effect of apigenin on acetaminophen-induced mouse acute liver injury and to investigate the potential mechanisms. A mouse model with acute liver injury was induced by intraperitoneally given acetaminophen 350 mg kg(-1) after oral administration of apigenin 100 and 200 mg kg(-1) for 7 days. The results showed that after treatment with apigenin, the levels of serum alanine aminotransferase and aspartate aminotransferase were gradually decreased, and the severity of liver injury was decreased. In particular, significant changes in liver necrosis were observed in the apigenin 200 mg kg(-1) group. Apigenin could gradually increase the hepatic glutathione reductase (GR) activity and reduced glutathione (GSH) content, and decrease the hepatic malondialdehyde content, but the activities of glutathione peroxidase and glutathione S-transferase in hepatic tissues between the model group and the apigenin-treated groups were not significantly different. It was concluded that apigenin could protect against acetaminophen-induced acute liver injury in mice, and the mechanisms might be associated with enhancing hepatic GSH content via increment of GR activity.

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Section: Discussionmentioning

confidence: 99%

Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity

et al. 2013

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“…It has been shown that a large dose of paracetamol administered to rats causes a decrease in concentration of glutathione (GSH) in liver cells [15,33]. The mentioned paper suggests that toxicity of paracetamol depends on a balance between the rate of reactive PC metabolite (NAPQI) formation and regeneration of the reduced glutathione [11,33]. Increase of glutathione-S-transferase activity in the liver of rats administered with paracetamol (as found in .…”

Section: Discussionmentioning

confidence: 86%

“…Accumulation of this metabolite can lead to liver necrosis [4,9]. NAPQI is coupled with glutathione in the presence of glutathione-S-transferase [10,11]. NAPQI is an inhibitor of the respiratory chain complex.…”

Section: Introductionmentioning

confidence: 99%

Long-term Exposure to Acetaminophen is a Crucial for Activity of Selected Antioxidative Enzymes and Level of Lipid Peroxidation Process in Rat Liver

Polaniak¹,

Bułdak²,

Jacheć³

et al. 2011

JBB

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Background: Our aim was to investigate the effect of intra-oesophageal acetaminophen instillation on the selected antioxidative enzymes activity: superoxide dismutase isoenzymes (MnSOD, Cu/ZnSOD), glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GR) and lipid peroxidation in rat liver after 4, 8 and 12 weeks of exposure. Material and methods: Male Wistar FL strain rats weighing 150-160 g were treated with paracetamol by intraoesophageal instillation at a dose of 2.4 g/kg b.w every day up to 12 weeks. During the whole experiment rats were kept in a night-and-day's cycle lasting twelve hours, with standard feed ad libitum. Rats were sacrificed after 4, 8 and 12 weeks of the study. The collected tissue liver was homogenized and the above mentioned enzymes were determined in the supernatants. Results: The current study revealed the presence of paracetamol-induced changes in the activities of antioxidative enzymes in comparison to the control values. Our results suggested that long term exposure to PC (8 and 12 weeks) decreased activity of GPX enzyme and increased activity of GST and GR enzymes as well as increased level of lipid peroxidation process in rat liver. These changes in the activity of antioxidative enzymes may be involved in paracetamol toxicity of the liver after a longer time of exposure to PC. The cited literature and our findings show that excessive use of paracetamol-containing preparations can have a harmful effect upon liver metabolism and suggest the need for further research.

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“…N-acetyl- p -benzoquinone imine is also one of the first phase metabolites of paracetamol detoxification in humans, excreted as a glutathione conjugate with urine (Tsikas et al 2011 ; Li et al 2014 ). It is defined as highly hepatotoxic (Bender and MacCrehan 2006 ; Hinson et al 2010 ; Tsikas et al 2011 ). Bender et al ( 2004 ) suggest that NAPQI may be a potent inhibitor of human topoisomerase IIα.…”

Section: Environmental Risk Of Monocyclic Non-steroidal Anti-inflammamentioning

confidence: 99%

Over-the-Counter Monocyclic Non-Steroidal Anti-Inflammatory Drugs in Environment—Sources, Risks, Biodegradation

Marchlewicz

Wojcieszyńska

2015

Water Air Soil Pollut

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Recently, the increased use of monocyclic non-steroidal anti-inflammatory drugs has resulted in their presence in the environment. This may have potential negative effects on living organisms. The biotransformation mechanisms of monocyclic non-steroidal anti-inflammatory drugs in the human body and in other mammals occur by hydroxylation and conjugation with glycine or glucuronic acid. Biotransformation/biodegradation of monocyclic non-steroidal anti-inflammatory drugs in the environment may be caused by fungal or bacterial microorganisms. Salicylic acid derivatives are degraded by catechol or gentisate as intermediates which are cleaved by dioxygenases. The key intermediate of the paracetamol degradation pathways is hydroquinone. Sometimes, after hydrolysis of this drug, 4-aminophenol is formed, which is a dead-end metabolite. Ibuprofen is metabolized by hydroxylation or activation with CoA, resulting in the formation of isobutylocatechol. The aim of this work is to attempt to summarize the knowledge about environmental risk connected with the presence of over-the-counter anti-inflammatory drugs, their sources and the biotransformation and/or biodegradation pathways of these drugs.

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In-source formation of N-acetyl-p-benzoquinone imine (NAPQI), the putatively toxic acetaminophen (paracetamol) metabolite, after derivatization with pentafluorobenzyl bromide and GC–ECNICI-MS analysis

Cited by 13 publications

References 30 publications

Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity

Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity

Long-term Exposure to Acetaminophen is a Crucial for Activity of Selected Antioxidative Enzymes and Level of Lipid Peroxidation Process in Rat Liver

Over-the-Counter Monocyclic Non-Steroidal Anti-Inflammatory Drugs in Environment—Sources, Risks, Biodegradation

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