N-acetyl-p-benzoquinoneimine

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. 

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. 

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 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. 

Weis, M., Kass, G. E. N., Orrenius, S., Moldeus, P. (1992). N-acetyl-p-benzoquinoneimine induces calcium release from mitochondria by stimulating pyridine nucleotide hydrolysis. J. Biol. Chem. 267, 804-809. 

Coles, B.,Wilson, I., Wardman, P., Hinson, J. A., Nelson, S. D., andKetterer, B. (1988)The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinoneimine with glutathione a stopped-flow kinetic study. Arch. Biochem. Biophys. 264, 253-260. 

Recent studies have shown that hamster liver microsomes convert N-hydroxyphenacetin but not acetaminophen to N-hydroxy-acetaminophen even though considerbly more acetaminophen is covalently bound to microsomal proteins than is N-hydroxy-phenacetin (35). Moreover, the chemically reactive metabolite of acetaminophen is apparently not formed by way of acetaminophen epoxide because the formation of 3-hydroxyacetaminophen is not blocked by glutathione, ascorbic acid or epoxide hydrolase and covalent binding of acetaminophen is not blocked by superoxide dismutase (3 ) Thus, the chemically reactive metabolite of acetaminophen remains unidentified. It is still possible that the intermediate is N-acetylimidoquinone (N-acetyl-p-benzoquinoneimine) because it reacts with glutathione to form a glutathione-acetaminophen conjugate, and is readily reduced to acetaminophen by ascorbic acid. If N-acetylimidoquinone is the major reactive metabolite, however, it must be formed by a hitherto unknown mechanism. 

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