Acetaminophen metabolism

Chen, C., Krausz, K. Idle, J. and Gonzalez, F.J. (2008) Identification of novel toxicity-assodated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2el-null mice. Journal of Biological Chemistry, 238 (8), 4543 559. 

Li Y, Wang E, Patten CJ, Chen L, Yang CS. Effects of flavonoids on cytochrome P450-dependent acetaminophen metabolism in rats and human liver microsomes. Drug Metab Dispos 1994 22(4) 566-571. 

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. 

Miners JO, Attwood J, Birkett DJ. Determinants of acetaminophen metabolism effect of inducers and inhibitors of drug metabolism on acetaminophen s metabolic pathways. Clin Pharmacol Ther 1984 35(4) 480-486. 

Park JM, Lin YS, Calamia JC, etal. (2003) Transiently altered acetaminophen metabolism after liver transplantation. Clin Pharmacol Ther 73 545-553. 

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... 

Anderson KE, Schneider J, Pantuck EJ, Pantuck CB, Mudge GH, Welch RM, Conney AH, Kappas A. 1983. Acetaminophen metabolism in subjects fed charcoal-broiled beef. Clin. Pharmacol. Ther. 34 369-74... 

Genter MB, Liang HC, Gu J, Ding X, Negishi M, et al. 1998. Role of CYP2A5 and 2G1 in acetaminophen metabolism and toxicity in the olfactory mucosa of the Cypla2(—/—) mouse. Biochem. Pharmacol. 55 1819-26... 

Figure 34-6 Pathways of acetaminophen metabolism. (From Mitchell JR,Thorgeirsson SS, Potter WZ, jollow Dj, Keiser H. Acetaminophen-induced hepatic injury Protective role of g/utat/iione in man and rationale for therapy. Clin PharmacolTher 1974 16 676.)...

Alcohol is metabolized to acetaldehyde by cytosolic ADH and the MEOS (primarily GYP 2E1— the same cytochrome p45o dependent enzyme involved with acetaminophen metabolism). Acetaldehyde is subsequently metabofized to acetyl-CoA by AADH. This is further broken dovra to acetate, which is either converted to carbon dioxide and water or enters the citric acid cycle to be converted to fatty acids. The latter is a major mechanism for induction of fatty liver by alcohol, but acetaldehyde is probably the primary toxin. It causes most of the injury to liver cells as well as the induction of collagen synthesis leading to fibrosis and, ultimately, cirrhosis. 

Holownia, A., Mapoles, J., Menez, J. F., Braszko, J. J. Acetaminophen metabolism and cytotoxicity in PC12 cells transfected with cytochrome P4502E1. J. Mol. Med. 1997, 75, 522-527. 

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

Baillie et al. [224] presented another example of the characterization of thioethers from acetaminophene, metabolically produced when high doses of analgesics (such as paracetamol) were administered. 

CAR in hepatocytes. However, PRIP is not required for nuclear translocation of CAR. Activation of CAR is known to increase acetaminophen hepatotoxicity by inducing acetaminophen-metabolizing enzymes in the liver [43]. Deficiency of PBP, but not of PRIP, abrogates acetaminophen hepatotoxicity [41],... 

The enzyme that produces NAPQI, CYP2E1, is induced by alcohol (see Chapter 25, MEOS). Thus, individuals who chronically abuse alcohol have an increased sensitivity to acetaminophen toxicity, because a higher percentage of acetaminophen metabolism is directed toward NAPQI, as compared with an individual with low levels of CYP2E1. Therefore, even recommended therapeutic doses of acetaminophen can be toxic to these individnals. 

The chronic abuse of alcohol predisposes to hepatic damage following overdose of acetaminophen because ethanol (A) Blocks acetaminophen metabolism Causes thiamine deficiency Displaces acetaminophen from plasma proteins Induces liver drug-metabolizing enzymes Inhibits renal clearance of acetaminophen... 

Dai G, He L, Chou N, Wan YJ (2006) Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse. Toxicol Sci 92(1) 33-41 Dambach DM, Durham SK, Laskin JD, Laskin DL (2006) Distinct roles of NF-kappaB p50 in the regulation of acetaminophen-induced inllanunatory mediator production and hepatotoxicity. Toxicol Appl Pharmacol 211(2) 157-165... 

Children younger than 10-12 years of age appear to be less susceptible to hepatotoxicity because of the smaller contribution of cytochrome P-450 to acetaminophen metabolism. 

PoulsonHE, RanekL, Jorgensen L. The influence of disulfiram on acetaminophen metabolism m.m2tn.Xenobiotica (1991) 21, 243-9. 

Mitchell MC, Hanew T, Meredith CG, Schenker S. Effects of oral contraceptive steroids on acetaminophen metabolism and elimination. Clin Pharmacol Ther (1983) 34,48-53. 

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