A-Acetyl-p-benzoquinone imine

Manno et al. [43] observed the formation of superoxide during the oxidation of arylamines by rat liver microsomes. Noda et al. [44] demonstrated that microsomes are able to oxidize hydrazine into a free radical. In contrast, hepatic cytochrome P-450 apparently oxidizes paracetamol (4 -hydroxyacetanilide) to A-acetyl-p-benzoquinone imine by a two-electron mechanism [45]. Younes [46] proposed that superoxide mediated the microsomal S -oxidation of thiobenzamide. 

The reaction of the lipid-regulator gemfibrozil with free chlorine yielded four chlorinated derivatives of this compound [94]. Chlorination of acetaminophen (paracetamol) generated 11 discernible DBFs, including the toxic compounds 1,4-benzoquinone and A-acetyl-p-benzoquinone imine and two ring chlorination products, chloro-4-acetamidophenol and dichloro -acetamidophenol [95]. 

Bioactivation is a classic toxicity mechanism where the functional group or the chemical structure of the drug molecule is altered by enzymatic reactions. For example, the enzymatic breakdown of the analgesic acetaminophen (paracetamol), where the aromatic nature and the hydroxyl functionality in paracetamol are lost, yields A -acetyl-p-benzoquinone imine, a hepatotoxic agent. Paracetamol can cause liver damage and even liver failure, especially when combined with alcohol. 

A small percentage of acetaminophen is metabolized by phase I oxidation with A-hydroxylation of the amide (8.81) (Scheme 8.22). Loss of water affords A-acetyl-p-benzoquinone imine (8.82). Benzoquinones are electron-deficient and strongly electrophilic, a trait of many toxic... 

SCHEME 11.9 Bioactivation of acetaminophen to form a reactive A-acetyl-p-benzoquinone imine (NAPQI) and trapping of the electrophilic intermediate by GSH. 

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. 

Figure 7.19 Proposed metabolic activation of paracetamol to a toxic, reactive intermediate /V-acetyl-p-benzoquinone imine (NAPQI). This can react with glutathione (GSH) to form a conjugate or with tissue proteins. Alternatively, NAPQI can be reduced back to paracetamol by glutathione, forming oxidized glutathione (GSSG).

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. 

The analgesic acetaminophen (4-hydroxyacetanilide, paracetamol) exhibits hepatotoxicity when administered in very high doses (approximately 250mg/kg in rat and about 13 g for a 75kg human ). The metabolite responsible is known to be the V-acetyl-p-benzoquinone imine (NAPQl) (Figure 33.21).45... 

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.

In many cases of severe hepatotoxicity, renal injury is also present and may range from oliguria to acute renal failure. The etiology of the renal injury may be a direct effect of a toxic metabolite of acetaminophen, M-acetyl-p-benzoquinone-imine (discussed in the next section), generated by renal cytochrome oxidase or a consequence of hepatic injury resulting in hepatorenal syndrome. Isolated cases of myocardial injury have been reported rarely. ... 

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... 

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. 

The metabolite to paracetamol ratio for glucuronides was twice as high in 10 patients treated with rifampicin 600 mg daily than in 14 healthy control subjects. In contrast the ratio for sulfates did not differ between the two groups. In a crossover study in healthy subjects, rifampicin 600 mg daily for 1 week, given before paracetamol 500 mg, had no effect on the formation of V-acetyl-p-benzoquinone imine (NAPQI) or the recovery of thiol... 

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