Disease relevance of N-Acetyl-p-benzoquinone

• Inhibition of toxicity was not due to alterations in acetaminophen metabolism since aminoguanidine had no effect on hepatocyte cytochrome P4502E1 protein expression or N-acetyl-p-benzoquinone-imine formation [1].
• Exposure of isolated hepatocytes to 400 microM 3,5-dimethyl N-acetyl-p-benzoquinone imine (3,5-diMe NAPQI), rapidly induced the formation of plasma membrane blebs [2].

Psychiatry related information on N-Acetyl-p-benzoquinone

• Chronic alcohol consumption may potentiate acetaminophen (APAP) hepatotoxicity through enhanced formation of N-acetyl-p-benzoquinone imine (NAPQI) via induction of cytochrome P450 2E1 (CYP2E1) [3].

High impact information on N-Acetyl-p-benzoquinone

• We report herein that the iminoquinone metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), inhibits both the isomerase and the biological activities of MIF [4].
• This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage [5].
• The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), that leads to gluthatione depletion has been suspected to be the main effector of hepatocyte apoptosis during APAP-induced ALF [6].
• The mechanism of N-acetyl-p-benzoquinone imine (NAPQI)-induced release of Ca2+ from rat liver mitochondria was investigated [7].
• Acetaminophen overdose causes severe hepatotoxicity in humans and laboratory animals, presumably by metabolism to N-acetyl-p-benzoquinone imine: and binding to cysteine groups as 3-(cystein-S-yl)acetaminophen-protein adduct [8].

Chemical compound and disease context of N-Acetyl-p-benzoquinone

• Depletion of intracellular glutathione augmented the toxicity of N-acetyl-p-benzoquinone imine (1.5-3-fold at 100 and 10 microM) [9].

Biological context of N-Acetyl-p-benzoquinone

• Our results suggest that acetaminophen and N-acetyl-p-benzoquinone imine exert their cytotoxic effects via a disruption of Ca2+ homeostasis secondary to the depletion of soluble and protein-bound thiols [10].
• OBJECTIVE: To determine in patients receiving isoniazid prophylaxis whether an increase in the CYP2E1 dependent formation clearance of acetaminophen (paracetamol) to N-acetyl-p-benzoquinone imine (NAPQI) occurs during a normal 24-hour isoniazid dose interval and whether the interaction is dependent on acetylation status [11].
• Detection of N-acetyl-p-benzoquinone imine produced during the hydrolysis of the model phenacetin metabolite N-(pivaloyloxy)phenacetin [12].
• In vitro exposure of intact mitochondria to N-acetyl-p-benzoquinone imine (NAPQI) with calcium caused mitochondrial swelling [13].
• Paracetamol was selected as a model-toxin, since it is known to be bioactivated by 3-methylcholanthrene inducible cytochromes P450 presumably to N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite which upon overdosage causes protein- and non-protein thiol-depletion, lipid peroxidation and cytotoxicity measured as LDH-leakage [14].

Anatomical context of N-Acetyl-p-benzoquinone

• Under comparable conditions N-acetyl-p-benzoquinoneimine had no effect on any of the hepatocyte cell lines [15].
• Effects of ethanol and inhibitors on the binding and metabolism of acetaminophen and N-acetyl-p-benzoquinone imine by hepatic microsomes from control and ethanol-treated rats [16].
• This suggests that N-acetyl-p-benzoquinoneimine does not readily transit the visceral yolk sac and would likely not be a major factor in APAP-elicited neural tube abnormalities unless generated in target tissues [17].
• To elucidate the P-450 forms involved in these divergent effects, rat liver microsomes, prepared after pretreatment with various inducers, were used to examine the effect of caffeine on N-acetyl-p-benzoquinone imine (NAPQI) formation [18].
• Differential effects of arylating and oxidizing analogs of N-acetyl-p-benzoquinoneimine on red blood cell membrane proteins [19].

Associations of N-Acetyl-p-benzoquinone with other chemical compounds

• Reactions of N-acetyl-p-benzoquinone imine with reduced glutathione, acetaminophen, and NADPH [20].
• However, with intra-amniotic microinjections, 3-hydroxyacetaminophen and N-acetyl-p-benzoquinoneimine were roughly equipotent for eliciting abnormal neurulation, whereas 3-methoxyacetaminophen required greater than 30-fold higher concentrations [17].
• HPLC analyses of acid supernatants from livers of mice treated with acetaminophen in vivo showed a peak that coeluted with an adduct generated in vitro by reaction of CoASH with N-acetyl-p-benzoquinone imine, but extensive efforts to characterize further the putative product formed in vivo have been unsuccessful [21].
• The involvement of cytochrome b5 in the formation of N-acetyl-p-benzoquinone imine (NAPQI) was implicated through a synergistic effect of NADH on the NADPH-supported reaction [22].
• The hepatotoxicity of acetaminophen is believed to be mediated by the metabolic activation of acetaminophen to N-acetyl-p-benzoquinone imine which covalently binds to cysteinyl residues on proteins as 3-(cystein-S-yl)acetaminophen adducts [23].

Gene context of N-Acetyl-p-benzoquinone

• This is thought to be mediated via the P450-generated reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI) [24].
• This study was conducted to determine the impact of knockout of selenium (Se)-dependent glutathione peroxidase-1 (GPX1(-/-)) or double knockout of GPX1 and copper, zinc (Cu,Zn)-super-oxide dismutase (SOD1) on cell death induced by acetaminophen (APAP) and its major toxic metabolite N-acetyl-P-benzoquinoneimine (NAPQI) [25].
• This was attributed to increased production of the toxic metabolite, N-acetyl-p-benzoquinoneimine, by cytochrome P450 (CYP)2E1 induction [26].
• These results support the hypothesis that the aromatic hydrocarbon receptor-independent induction of cytochrome P450 1A2 enzyme leads to accumulation of sufficient N-acetyl-p-benzoquinone in the liver and cataract development in the eye [27].
• Neither the incubation of N-acetyl-p-benzoquinone imine nor that of N-acetyl-2,6-dimethyl-p-benzoquinone imine with NADPH-cytochrome P-450 reductase yielded a detectable concentration of the corresponding phenoxyl free radical [28].

References