Benzoquinoneimine

MPP = l-methyl-4-phenylpyridiniiim NAPBQI = N-acet l-p-benzoquinoneimine. Source Modified from Gregus and Klaassen. ... 

In contrast, soft electrophiles react with nucleophilic SH groups in GSH and proteins. Soft electrophiles are typically cytotoxic, such as the metabolite of paracetamol, N-acetyl-p-benzoquinoneimine (Fig. 4.73) (see also chap. 7). So reactivity with GSH depends on the hardness/softness of the electrophile. 

Side-effects are rare and may include hematological reactions, leucopenia, agranulocytosis and other hypersensitivity reactions. Paracetamol has a narrow therapeutic dose range and overdosage induces severe liver and renal damage (Lewis and Paloucek, 1991) via accumulation of a toxic metabolite, N- acetyl-benzoquinoneimine (NABQI). Acetylcysteine or methionine, which increase glutathione conjugation of the metabolite, are used as the antidote. 

Bistriazo 4 trimethylammonium l,4 benzo quinone. See 2,6-Diazido-4-trimethylammonium -1,4-benzoquinone under Benzoquinoneimine and Derivatives... 

Figure 22.2 shows a schematic representation of the enzymatic process between paracetamol and peroxidase catalyzed by the zucchini tissue powder incorporated into the Nujol/graphite electrode and also the electrochemical reduction of V-acetyl-p-benzoquinoneimine to paracetamol at a potential of —0.12 V. 

FIGURE 15-3 Acetaminophen metabolism. In the liver, acetaminophen is metabolized to a toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is quickly detoxified by conjugation with glutathione (GSH), forming mercapturic acid, which is eliminated via the urine. High doses of acetaminophen or liver dysfunction can result in accumulation of NAPQI and subsequent toxicity to liver proteins. 

Vitamin B6 /V,2,6-Trichloro-p-benzoquinoneimine (0.1% in ethanol) Blue spots after exposure to ammonia 3... 

The mechanism of acetaminophen toxicity has been studied extensively in experimental animals. Oxidation of acetaminophen in the liver via cytochrome P450 results in the formation of a cytotoxic electrophile, N-acetyl-p-benzoquinoneimine (NAPQI), that binds to hepatic protein. In the kidney, the formation of a one-electron oxidation product, namely N-acetyl-benzosemiquinoneimine radical, occurs via prostaglandin H synthase. This free radical binds to renal proteins and damages the renal medulla. 

An example of a popular pharmaceutical with a toxic metabolite is acetaminophen (2, 3). A portion of the acetaminophen metabolized in the liver is converted to a reactive intermediate/ N-acetyl-p-benzoquinoneimine (NAPQI)/ which is an excellent substrate for nucleophilic attack by free sulfhydryl groups in proteinS/ as shown in Scheme 11.4. By substituting a high concentration of an alternative... 

The biotransformation of the toxic oil contaminant PAP to the L-tryptophan contaminant PAA may link TOS and EMS to a common chemical agent, namely PAA. Both PAP and PAA are metabolized further to the p-hydroxylated forms, FIPAP and FIPAA (Figure 7). Such compounds readily autoxi-dize to the benzoquinoneimine, which is reactive toward nucleophiles such as the sulfhydryl and amino moieties present on many biological molecules. Thus, upon oxidization, FIPAA and FIPAP may react with macromolecules as a hapten to form immunogenic targets. HPAA possesses some chemical properties... 

The mechanism of acute acetaminophen nephrotoxicity is related to the bioactivation of acetaminophen and/or its metabolites to highly reactive species which are capable of arylating renal macromolecules or generating reactive oxygen species. Acetaminophen hepatotoxicity is the result of conversion of acetaminophen to the reactive intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can covalently bind to hepatic macromolecules. It is less clear what role formation of NAPQI in the kidney plays in acetaminophen nephrotoxicity. In some species (e.g., the Fischer 344 rat) deacetylation appears to be an important biotransformation step in acetaminophen nephrotoxicity, while in other species (e.g., the CD-I mouse), bioactivation does not appear to require deacetylation of acetaminophen before the ultimate nephrotoxicant species is produced. Therefore, the role of NAPQI in acute acetaminophen nephrotoxicity might be species dependent. 

The mechanism of 4-aminophenol nephrotoxicity remains to be determined with certainty. The current hypothesis suggests that 4-aminophenol is oxidized by cytochrome P450 isozymes or peroxidases to p-benzoquinoneimine which can arylate renal mac-romolecules and/or redox cycle between 4-aminophenol and p-benzoquinoneimine to form reactive oxygen species. Recent studies have suggested that... 

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