N-acetyl-p-benzoquinone imine

Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and Nelson, S.D. (1984). N-Acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl Acad. Sci. USA 81, 1327-1331. 

NAP Neutrophil-activating peptide NAPQI N-acetyl-p-benzoquinone imine... 

Bedner M, MacCrehan WA (2005) Transformation of acetaminophen by chlorination produces the toxicants 1,4-benzoquinone and N-acetyl-p-benzoquinone imine. Environ Sci Technol 40 516-522... 

Synthesis and Kinetics of Hydrolysis of 3,5-Dimethyl-N-acetyl-p-benzoquinone Imine 235... 

Chen W, Shockcor JP, Tonge R, Hunter A, Gartner C, Nelson SD. Protein and nonprotein cysteinyl thiol modification by N-acetyl-p-benzoquinone imine via a novel ipso adduct. Biochemistry 1999 38 8159-66. 

Albano E, Rundgren M, Flarvison PJ, Nelson SD, Moldeus P. Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol Pharmacol 1985 28 306-315. 

Figure 35.13 Acetaminophen toxicity. A minor metabolic product of acetaminophen is N-acetyl-p-benzoquinone imine, This metabolite is conjugated to glutathione. Large doses of acetaminophen can deplete liver glutathione stores.

Perhaps N-acetylcysteine would conjugate to some of the N-acetyl-p benzoquinone imine that is produced by the metabolism of acetaminophen, thereby preventing the depletion of the liver s supply of glutathione. 

FIGURE 7.11 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate N-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins,... 

In other instances, a nontoxic parent compound is transformed by CYP into a reactive metabolite that is toxic to the mitochondria. This is seen with acetaminophen, which is transformed by CYP2E1 to the chemically reactive, N-acetyl-p-benzoquinone imine. The hepatic toxicity of acetaminophen is increased in alcoholics (Seef et al. 1986). Ethanol abuse increases CYP2E1 in the endoplasmic reticulum and in the mitochondria (Robin et al. 2005). The mitochondrial localization of CYP2E1 may lead to the in situ generation of reactive metabolites of acetaminophen in the mitochondria, where the metabolite may trigger MPT (Weis et al. 1992 Masubuchi et al. 2005). Mitochondria also contain other inducible CYPs, such as CYPlAl and CYP2B1 (Anandatheerthavarada et al. 1997 Sepuri et al. 2007). The concomitant administration of CYP-inducers, phenobarbital or phenytoin increases the hepatotoxicity of valproic acid, which is transformed by microsomal and mitochondrial CYPs and then p-oxidation enzymes into a reactive... 

Weis M, Kass GE, Orrenius S, Moldeus P (1992) N-acetyl-p-benzoquinone imine induces Ca release from mitochondria by stimulating pyridine nucleotide hydrolysis. J Biol Chem 267 804-809... 

Fig. 3 Mechanistic determinants in acetaminophen-induced hepatic necrosis. APAP Acetaminophen, iVAFg/N-Acetyl-p-benzoquinone imine, CYP cytochrome P-450, G5//reduced glutathione, ROS reactive oxygen species, RNS reactive nitrogen species, om outer membrane, im inner membrane, MPT mitochondrial permeability transition, BAX Bcl-2-associated X protein...

Dahlin DC, Nelson SD (1982) Synthesis, decomposition kinetics, and preliminary toxicological studies of pure N-acetyl-p-benzoquinone imine, a proposed toxic metabolite of acetaminophen. J Med Chem 25 885-886... 

Dahlin DC, Miwa GT, Lu AY, Nelson SD (1984) N-acetyl-p-benzoquinone imine a cytochrome P-450-mediated oxidation product of acetaminophen. Proc Natl Acad Sci USA 81 1327-1331 Davem TJ 2nd, James LP, Hinson JA, Poison J, Larson AM, Fontana RJ, Lalani E, Munoz S, Shakil AO, Lee WM (2006) Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology 130 687-694 Davidson DG, Eastham WN (1966) Acute liver necrosis following overdose of paracetamol. Br Med J 5512 497 99... 

Acetaminophen (paracetamol) is a commonly used analgesic which is hepatotoxic at high doses in humans and in laboratory animals. Toxicity is believed to be mediated by the reactive metabolite N-acetyl-p-benzoquinone imine which binds to protein thiols as 3-(cystein-S-yl)acetaminophen adducts. Ultrasensitive immimoassays for 3-(with parallel elevations in serum adducts and serum levels of the liver-specific transaminase ALT. This suggested that the serum adducts were of hepatic origin and could be monitored as a biomarker of acetaminophen toxicity. Analysis of serum samples from acetaminophen overdose patients demonstrated a positive correlation between immunochemically detectable serum adducts and hepatotoxicity. 

Acetaminophen-induced hepatotoxicity is mediated by cytochrome P450 metabolism to N-acetyl-p-benzoquinone imine. Following low doses of acetaminophen the metabolite is efficiently detoxified by glutathione (GSH) however, following large doses hepatic GSH is depleted and to N-acetyl-p-benzo-quinone imine covalently binds to proteins as acet-... 

The enzyme induction may increase toxic metabolites because of some drags are transformed into toxic metabolites. For example, analgesic acetaminophen is mainly converted into non-toxic metabolites, but its small amount is transformed by CYP2E1 into a cytotoxic metabolite N-acetyl-p-benzoquinone imine. Enzyme inductors may increase the formation of toxic metabolite and increase the risk of hepatotoxicity and damage of other organs. 

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