A?-Acetyl benzoquinoneimine

Pathophysiology Acetaminophen is metabolized via the cytochrome P450 enzymes into a deleterious product A-acetyl benzoquinoneimine, an unstable intermediate, which causes arylated derivatives of protein, lipid, ribonucleic acid (RNA), and deoxyribonucleic acid (DNA), causing destruction of these compounds. Because the Uver has high levels of cytochrome P450 enzymes, it is the major organ affected by acetaminophen overdose. 

D. Acetaminophen is not itself toxic, but its intermediate metabohte A-acetyl benzoquinoneimine can be toxic unless it is adequately conjugated. In the case presented, a high dose of acetaminophen overwhelmed the conjugative processes, allowing the toxic intermediate to interact with body components and thus causing the nausea, vomiting, and elevated blood enzymes observed. 

Acetaminophen is oxidized by the cytochrome P450 system, yielding the deleterious product A-acetyl benzoquinoneimine, an unstable intermediate that can react with cellular macromolecules and thus damage them. 

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. 

C. M-acetyl benzoquinoneimine is toxic, whereas acetaminophen glu-curonide, acetaminophen sulfate, and acetaminophen glutathionate are nontoxic acetaminophen conjugates. A -acetyl-p-aminophenol is another name for acetaminophen. 

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. 

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... 

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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