The molecular toxicology of acetaminophen

Drug Metabolism Reviews

Volumn 37, Issue 4, 2005, Pages 581-594

  Josephy, P David ^a  

^a UNIVERSITY OF GUELPH   (Canada)

Author keywords

Actaminophen; Covalent binding; Hepatotoxicity; P450

Indexed keywords

ACETYLSALICYLIC ACID; ANALGESIC AGENT; CYCLOOXYGENASE 1 INHIBITOR; CYCLOOXYGENASE 2 INHIBITOR; CYTOCHROME P450; GLUTATHIONE; IBUPROFEN; N ACETYL 1,4 BENZOQUINONE IMINE; NAPROXEN; NONSTEROID ANTIINFLAMMATORY AGENT; PARACETAMOL; PHENACETIN; QUINONE DERIVATIVE;

ALCOHOL CONSUMPTION; ANALGESIC ACTIVITY; ANTIPYRETIC ACTIVITY; CATALYSIS; COVALENT BOND; DRUG EFFICACY; DRUG ELIMINATION; DRUG INTOXICATION; DRUG MECHANISM; DRUG METABOLISM; DRUG OVERDOSE; DRUG OXIDATION; DRUG PROTEIN BINDING; DRUG SAFETY; GLUTATHIONE METABOLISM; HUMAN; KNOCKOUT MOUSE; LIVER INJURY; LIVER TOXICITY; MEDICAL RESEARCH; METHEMOGLOBINEMIA; NONHUMAN; PROTEIN BINDING; PROTEIN TARGETING; REVIEW;

ACETAMINOPHEN; ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; CYTOCHROME P-450 ENZYME SYSTEM; DRUG INTERACTIONS; ETHANOL; HEPATITIS, TOXIC; HUMANS; OXIDATION-REDUCTION; PROTEIN BINDING;

EID: 30344461594     PISSN: 03602532     EISSN: 10979883     Source Type: Journal    
DOI: 10.1080/03602530500205200     Document Type: Review

References (69)

1. Berenbaum, F. (2004). COX-3: fact or fancy? Jt. Bone Spine. 71:451-453.
2. Berg, J. M., Tymoczko, J. L., Stryer, L. (2001). Biochemistry. New York: W.H. Freeman.
3. Bessems, J. G., Vermeulen, N. P. (2001). Paracetamol (acetaminophen)- induced toxicity: molecular and biochemical mechanisms, analogues and protective approaches. Crit. Rev. Toxicol. 31:55-138.
4. Boréus, L. O., Sandberg, F. (1953). A comparison of some pharmacological effects of acetophenetidin and N-acetyl-p-aminophenol. Adv. Physiol. Scand. 28:261-265.
5. Bromer, M. Q., Black, M. (2003). Acetaminophen hepatotoxicity. Clin. Liver Dis. 7:351-367.
6. Büch, H., Pfleger, K., Rummel, W., Ullrich, V., Hey, D., Staudinger, H. (1967). Studies on the oxidative metabolism of phenacetin in rats (in German). Biochem. Pharmacol. 16:2247-2256.
7. Calder, I. C., Hart, S. J., Healey, K., Ham, K. N. (1981). N-hydroxyacetaminophen: a postulated toxic metabolite of acetaminophen. J. Med. Chem. 24:988-993.
8. Chandrasekharan, N. V., Dai, H., Roos, K. L., Evanson, N. K., Tomsik, J., Elton, T. S., Simmons, D. L. (2002). COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc. Natl. Acad. Sci. U. S. A. 99:13926-13931.
9. Chen, W., Koenigs, L. L., Thompson, S. J., Peter, R. M., Rettie, A. E., Trager, W. F., Nelson, S. D. (1998). Oxidation of acetaminophen to its toxic quinone imine and nontoxic catechol metabolites by baculovirus-expressed and purified human cytochromes P450 2E1 and 2A. Chem. Res. Toxicol. 11:295-301.
10. Coen, M., Lenz, E. M., Nicholson, J. K., Wilson, I. D., Pognan, F., Lindon, J. C. (2003). An integrated metabonomic investigation of acetaminophen toxicity in the mouse using NMR spectroscopy. Chem. Res. Toxicol. 16:295-303.
11. Coles, B., Wilson, I., Wardman, P., Hinson, J. A., Nelson, S. D., Ketterer, B. (1988). The spontaneous and enzymatic reaction of N-acetyl-p-benzoquinonimine with glutathione: a stopped-flow kinetic study. Arch. Biochem. Biophys. 264:253-260.
12. Corcoran, G. B., Mitchell, J. R., Vaishnav, Y. N., Horning, E. C. (1980). Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinoneimine. Mol. Pharmacol. 18:536-542.
13. Costa, E., Karczmar, A. G., Vesell, E. S. (1989). Bernard B. Brodie and the rise of chemical pharmacology. Annu. Rev. Pharmacol. Toxicol. 29:1-21.
14. Couzin, J. (2005). Drug safety. FDA panel urges caution on many anti-inflammatory drugs. Science 307:1183-1185.
15. Crofford, L. J. (1997). COX-1 and COX-2 tissue expression: implications and predictions. J. Rheumatol. 24(Suppl. 49):15-19.
16. Dahlin, D. C., Miwa, G. T., Lu, A. Y., Nelson, S. D. (1984). N-Acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Natl. Acad. Sci. U. S. A. 81:1327-1331.
17. de Morais, S. M., Wells, P. G. (1989). Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency. Hepatology 10:163-167.
18. de Morais, S. M., Chow, S. Y., Wells, P. G. (1992a). Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase. Toxicol. Appl. Pharmacol. 117:81-87.
19. de Morais, S. M., Uetrecht, J. P., Wells, P. G. (1992b). Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 102:577-586.
20. Dinchuk, J. E., Liu, R. Q., Trzaskos, J. M. (2003). COX-3: in the wrong frame in mind. Immunol. Lett. 86:121.
21. Dong, H., Haining, R. L., Thummel, K. E., Rettie, A. E., Nelson, S. D. (2000). Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen. Drug Metab. Dispos. 28:1397-1400.
22. Estabrook, R. W. (2003). A tribute to James Robert Gillette. Drug Metab. Dispos. 31:1459-1460.
23. Gaakeer, H. A., De Ruiter, H. J. (1979). Carcinoma of the renal pelvis following the abuse of phenacetin-containing analgesic drugs. Br. J. Urol. 51:188-192.
24. Gemborys, M. W., Gribble, G. W., Mudge, G. H. (1978). Synthesis of N-hydroxyacetaminophen, a postulated toxic metabolite of acetaminophen, and its phenolic sulfate conjugate. J. Med. Chem. 21:649-652.
25. Gyamlani, G. G., Parikh, C. R. (2002). Acetaminophen toxicity: suicidal vs. accidental. Crit. Care. 6:155-159.
26. Hazelton, G. A., Hjelle, J. J., Klaassen, C. D. (1986). Effects of cysteine pro-drugs on acetaminophen-induced hepatotoxicity. J. Pharmacol. Exp. Ther. 237:341-349.
27. Hinson, J. A. (1983). Reactive metabolites of phenacetin and acetaminophen: a review. Environ. Health Perspect. 49:71-79.
28. Hinson, J. A., Pike, S. L., Pumford, N. R., Mayeux, P. R. (1998). Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice. Chem. Res. Toxicol. 11:604-607.
29. Hinson, J. A., Reid, A. B., McCullough, S. S., James, L. P. (2004). Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab. Rev. 36:805-822.
30. Hoffmann, K. J., Streeter, A. J., Axworthy, D. B., Baillie, T. A. (1985). Identification of the major covalent adduct formed in vitro and in vivo between acetaminophen and mouse liver proteins. Mol. Pharmacol. 27:566-573.
31. Holtzman, J. L. (1995). The role of covalent binding to microsomal proteins in the hepatotoxicity of acetaminophen. Drug Metab. Rev. 27:277-297.
32. Jaeschke, H., Knight, T. R., Bajt, M. L. (2003). The role of oxidant stress and reactive nitrogen species in acetaminophen hepatotoxicity. Toxicol. Lett. 144:279-288.
33. James, L. P., Mayeux, P. R., Hinson, J. A. (2003). Acetaminophen-induced hepatotoxicity. Drug Metab. Dispos. 31:1499-1506.
34. Jollow, D. J., Mitchell, J. R., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B. (1973). Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. 187:195-202.
35. Kolb, F. A., Zhang, H., Jaronczyk, K., Tahbaz, N., Hobman, T. C., Filipowicz, W. (2005). Human dicer: purification, properties, and interaction with PAZ PIWI domain proteins. Methods Enzymol 392:316-336.
36. Liu, L., Klaassen, C. D. (1996). Different mechanism of saturation of acetaminophen sulfate conjugation in mice and rats. Toxicol. Appl. Pharmacol. 139:128-134.
37. Mann, C. C., Plummer, M. L. (1991). The Aspirin Wars: Money, Medicine, and 100 Years of Rampant Competition. New York: Knopf.
38. Martin, C. N., Garner, R. C. (1987). The identification and assessment of covalent binding in vitro and in vivo. In: Snell, K., Mullock, B., eds. Biochemical Toxicology: A Practical Approach. Oxford: IRL Press. pp. 109-128.
39. Mason, R. P., Fischer, V. (1986). Free radicals of acetaminophen: their subsequent reactions and toxicological significance. Fed. Proc. 45:2493-2499.
40. McClain, C. J., Kromhout, J. P., Peterson, F. J., Holtzman, J. L. (1980). Potentiation of acetaminophen hepatotoxicity by alcohol. JAMA 244:251-253.
41. McClain, C. J., Price, S., Barve, S., Devalarja, R., Shedlofsky, S. (1999). Acetaminophen hepatotoxicity: an update. Curr. Gastroenterol. Rep. 1:42-49.
42. McGirr, L. G., Suhrahmanyam, V. V., Moore, G. A., O'Brien, P. J. (1986). Peroxidase-catalyzed-3-(glutathion-S-yl)-p, p′-biphenol formation. Chem. Biol. Interact. 60:85-99.
43. McJunkin, B., Barwick, K. W., Little, W. C., Winfield, J. B. (1976). Fatal massive hepatic necrosis following acetaminophen overdose. JAMA 236:1874-1875.
44. McMurray, R. W., Hardy, K. J. (2002). Cox-2 inhibitors: today and tomorrow. Am. J. Med. Sci. 323:181-189.
45. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B. (1973a). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Ther. 187:185-194.
46. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., Brodie, B. B. (1973b). Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 187:211-217.
47. Mitchell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J., Vane, J. R. (1993). Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl. Acad. Sci. U. S. A. 90:11693-11697.
48. Morris, M. E., Levy, G. (1983). Serum concentration and renal excretion by normal adults of inorganic sulfate after acetaminophen, ascorbic acid, or sodium sulfate. Clin. Pharmacol. Ther. 33:529-536.
49. Nohmi, T., Mizokami, K., Kawano, S., Fukuhara, M., Ishidate, M. J. (1987). Metabolic activation of phenacetin and phenetidine by several forms of cytochrome P-450 purified from liver microsomes of rats and hamsters. Jpn. J. Cancer Res. 78:153-161.
50. Quellet, M., Percival, M. D. (2001). Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch. Biochem. Biophys. 387:273-280.
51. Paulus, H. E., Whitehouse, M. W. (1973). Nonsteroid anti-inflammatory agents. Annu. Rev. Pharmacol. 13:107-125.
52. Potter, W. Z., Davis, D. C., Mitchell, J. R., Jollow, D. J., Gillette, J. R., Brodie, B. B. (1973). Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-mediated covalent binding in vitro. J. Pharmacol. Exp. Ther. 187:203-210.
53. Reid, A. B., Kurten, R. C., McCullough, S. S., Brock, R. W., Hinson, J. A. (2005). Mechanisms of acetaminophen-induced hepatotoxicity: role of oxidative stress and mitochondrial permeability transition in freshly isolated mouse hepatocytes. J Pharmacol. Exp. Ther. 312:509-516.
54. Roberts, D. W., Bucci, T. J., Benson, R. W., Warbritton, A. R., McRae, T. A., Pumford, N. R., Hinson, J. A. (1991). Immunohistochemical localization and quantification of the 3-(cystein-S-yl)-acetaminophen protein adduct in acetaminophen hepatotoxicity. Am. J. Pathol. 138:359-371.
55. Ruepp, S. U., Tonge, R. P., Shaw, J., Wallis, N., Pognan, F. (2002). Genomics and proteomics analysis of acetaminophen toxicity in mouse liver. Toxicol. Sci. 65:135-150.
56. Rumack, B. H. (2002). Acetaminophen hepatotoxicity: the first 35 years. J. Toxicol., Clin. Toxicol 40:3-20.
57. Savides, M. C., Oehme, F. W., Nash, S. L., Leipold, H. W. (1984). The toxicity and biotransformation of single doses of acetaminophen in dogs and cats. Toxicol. Appl. Pharmacol. 74:26-34.
58. Schwab, J. M., Beiter, T., Linder, J. U., Laufer, S., Schulz, J. E., Meyermann, R., Schluesener, H. J. (2003). COX-3 - a virtual pain target in humans? FASEB J 17:2174-2175.
59. Sheen, C. L., Dillon, J. F., Bateman, D. N., Simpson, K. J., MacDonald, T. M. (2002). Paracetamol-related deaths in Scotland, 1994-2000. Br. J. Clin. Pharmacol. 54:430-432.
60. Singer, A. J., Carracio, T. R., Mofenson, H. C. (1995). The temporal profile of increased transaminase levels in patients with acetaminophen-induced liver dysfunction. Ann. Emerg. Med. 26:49-53.
61. Smilkstein, M. J., Bronstein, A. C., Linden, C., Augenstein, W. L., Kulig, K. W., Rumack, B. H. (1991). Acetaminophen overdose: a 48-hour intravenous N-acetylcysteine treatment protocol. Ann. Emerg. Med. 20:1058-1063.
62. Snyder, S. H. (2005). Obituary: Julius Axelrod (1912-2004). Nature 433:593.
63. Streeter, A. J., Dahlin, D. C., Nelson, S. D., Baillie, T. A. (1984). The covalent binding of acetaminophen to protein. Evidence for cysteine residues as major sites of arylation in vitro. Chem. Biol. Interact. 48:349-366.
64. Vane, J. R. (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat. New Biol. 231:232-235.
65. Vane, J. R., Bakhle, Y. S., Botting, R. M. (1998). Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38:97-120.
66. Veronese, M. E., McLean, S., D'Souza, C. A., Davies, N. W. (1985). Formation of reactive metabolites of phenacetin in humans and rats. Xenobiotica 15:929-940.
67. Zaher, H., Buters, J. T. M., Ward, J. M., Bruno, M. K., Lucas, A. M., Stern, S. T., Cohen, S. D., Gonzalez, F. J. (1998). Protection against acetaminophen toxicity in CYP1A2 and CYP2E1 double-null mice. Toxicol. Appl. Pharmacol. 152:193-199.
68. Zhang, J., Huang, W., Chua, S. S., Wei, P., Moore, D. D. (2002). Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science 298:422-424.
69. Zhao, P., Kalhorn, T. F., Slattery, J. T. (2002). Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver. Hepatology 36:326-335.