N-acetyl-p-benzoquinone

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... 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

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. 

Cytochrome P-450 and cysteine conjugate p-lyse are primarily localized in the proximal tubules, and these enzymes also contribute to the susceptibility of the proximal tubule to toxicant injury. Specifically, widely used industrial solvents such as chloroform produce tubular nephrotoxicity via cytochrome P-450 activation, and haloaUcanes and haloalkenes (e.g. trichloroethylene) are rendered toxic by cysteine conjugate (3-lyse activation [24,24a]. In addition, overdoses of acetaminophen (APAP) cause nephrotoxicity that is characterized by proximal tubular necrosis [25]. APAP undergoes cytochrome P-450-mediated activation to produce a toxic electrophile, N-acetyl-p-benzoquinon-eimine (NAPQI) [25a]. Although NAPQI is extremely reactive, it is detoxified by conjugation with reduced GSH unless NAPQI is formed in excess of the cellular capacity for GSH conjugation. The excess NAPQI is available to bind to critical cellular proteins and to induce oxidative stress, resulting in disruption of cellular homeostasis and tubular injury [26]. 

USA). Phenacetin is the prodrug of paracetamol, and has known toxic actions in uncontrolled general use - principally renal and hepatic toxic actions, and propensity to cause methaemoglobinaemia. However, now that paracetamol is in uncontrolled general use, it too has proved to have renal and hepatic toxic actions, especially in overdose and largely due to production of a toxic metabolite N-acetyl-p-benzoquinone. Paracetamol is an effective weak analgesic that does not cause gastric irritation, and is a useful... 

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 10-2. Pathway of acetaminophen metabolism and basis for hepatotoxicity. (NAPQI, N-acetyl-p-benzoquInone-lmlne, a reactive acetaminophen metabolite.)... 

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-... 

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