Involvement of Prostaglandin Synthase in the Metabolic Activation of Acetaminophen and Phenacetin

  • Peter Moldéus
  • Roger Larsson
  • David Ross
Part of the Prostaglandins, Leukotrienes, and Cancer book series (PLAC, volume 2)

Abstract

Acetaminophen (paracetamol, N-acetyl-p-aminophenol) and phenacetin (4-ethoxyacetamide) are analgesic and antipyretic drugs. Acetaminophen is widely used whereas phenacetin has been withdrawn from the market in most countries.

Keywords

Arachidonic Acid Single Strand Break Analgesic Nephropathy Thiyl Radical Linolenic Acid Hydroperoxide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Davidson D, Eastham W: Acute liver necrosis following overdose of paracetamol. Brit Med J (2): 497–499, 1966.PubMedCrossRefGoogle Scholar
  2. 2.
    Brown RAG: Hepatic and renal damage with paracetamol overdosage. J Clin Pathol (21): 793, 1968.PubMedCrossRefGoogle Scholar
  3. 3.
    Boyer TD, Rouff SL: Acetaminophen-induced hepatic necrosis and renal failure. J Amer Med Assoc (218): 440–441, 1971.CrossRefGoogle Scholar
  4. 4.
    Proudfoot AT, Wright N: Acute paracetamol poisoning. Brit Med J (3): 557–558, 1970.PubMedCrossRefGoogle Scholar
  5. 5.
    Prescott LF, Wright N, Roscoe P, Brown SS: Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet (1): 519–522, 1971.PubMedCrossRefGoogle Scholar
  6. 6.
    Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB: Acetaminophen-induced hepatic necrosis II, Role of covalent binding in vivo. J Pharmacol Exp. Ther (187): 195–202, 1973.PubMedGoogle Scholar
  7. 7.
    Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB: Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J Pharmacol Exp Ther (187): 185–194, 1973.PubMedGoogle Scholar
  8. 8.
    Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB: Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther (187): 211–217, 1973.PubMedGoogle Scholar
  9. 9.
    Moldéus P: Paracetamol metabolism and toxicity in isolated hepatocytes from rat and mouse. Biochem Pharmacol (27): 2859–2863, 1978.PubMedCrossRefGoogle Scholar
  10. 10.
    McMurtry RJ, Snodgrass WR, Mitchell JR: Renal necrosis, glutathione depletion and covalent binding after acetaminophen. Toxicol Appl Pharmacol (46): 87–100, 1978.PubMedCrossRefGoogle Scholar
  11. 11.
    Gabriel R, Caldwell J, Hartley RB: Acute tubular necrosis, caused by therapeutic doses of paracetamol? Clin Nephr (18): 269–271, 1982.Google Scholar
  12. 12.
    Cobden I, Record CO, Ward MK, Kerr DNS: Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Brit Med J (284): 21–22, 1982.CrossRefGoogle Scholar
  13. 13.
    Prescott LF, Proudfoot AT, Creegen RJ: Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Brit Med J (284): 421–422, 1982.CrossRefGoogle Scholar
  14. 14.
    Duggin GG: Mechanisms in the development of analgesic nephropathy. Kidney Int (18): 553–561, 1980.PubMedCrossRefGoogle Scholar
  15. 15.
    Stewart JH: Analgesic abuse and renal failure in Australasia. Kidney Int (13): 72–78, 1978.PubMedCrossRefGoogle Scholar
  16. 16.
    Spühler O, Zollinger HV: Die chronische-interstitille Nephritis. Z Klin Med (151): 1–9, 1953.PubMedGoogle Scholar
  17. 17.
    Bengtsson U: A comparative study of chronic non-obstructive pyelonephritis and renal papillary necrosis. Acta Med Scand (Suppl) (388): 5–71, 1962.Google Scholar
  18. 18.
    Hultengren N, Lagergren C, Ljungqvist A: Carcinoma of the renal pelvis in renal papillary necrosis. Acta Chir Scand (130): 314–320, 1965.Google Scholar
  19. 19.
    Johansson S, Wahlqvist, L: Tumorus of urinary bladder and ureter associated with abuse of phenacetin-containing analgesics. Acta Pathol Microbiol Scand Sect A (85): 768–774, 1977.Google Scholar
  20. 20.
    Isaka H, Yoshii H, Otsuji A, Koike M, Nagai Y, Koura M, Sugiyasu K, Kanabayaishi T: Tumors of Sprague-Dawley rats induced by long-term feeding of phenacetin. Gann (70): 29–36, 1979.PubMedGoogle Scholar
  21. 21.
    Johansson SL: Carcinogenicity of analgesics: long-term treatment of Sprague-Dawley rats with phenacetin, phenazone, caffeine and paracetamol (acetaminophen). Int J Cancer (27): 521–529, 1981.PubMedCrossRefGoogle Scholar
  22. 22.
    Smith RL, Timbrell JA: Factors affecting the metabolism of phenacetin. I. Influence of dose, chronic dosage, route of administration and species on the metabolism of (1–14C-acetyl)phenacetin. Xenobiotica (4): 489–501, 1974.PubMedCrossRefGoogle Scholar
  23. 23.
    Klutch A, Harfenist M, Conney AH: 2-hydroxy-acetophenetidine, a new metabolite of acetophenetidine. J Med Chem (9): 63–66, 1966.CrossRefGoogle Scholar
  24. 24.
    Nery R: Some new aspects of the metabolism of phenacetin in the rat. Biochem J (122): 317–326, 1971.PubMedGoogle Scholar
  25. 25.
    Calder IC, Creek MJ, Williams PJ, Funder CC, Green CR, Ham KN, Tange JD: N-hydroxylation of p-acetophenetidide as a factor in nephrotoxicity. J Med Chem (16): 499–502, 1973.PubMedCrossRefGoogle Scholar
  26. 26.
    Calder IC, Goss DE, Williams PJ, Funder CC, Green CR, Ham KN, Tange JD: Neoplasia in the rat induced by Nhydroxyphenacetin, a metabolite of phenacetin. Pathology (8): 1–6, 1976.PubMedCrossRefGoogle Scholar
  27. 27.
    Mulder GJ, Hinson JA, Gillette JR: Conversion of the N-Oglucuronide and N-O-sulfate conjugates of N-hydroxyphenacetin to reactive intermediates. Biochem Pharmacol (27): 1641–1649, 1978.PubMedCrossRefGoogle Scholar
  28. 28.
    Vaught JB, McGarvey PB, Lee M-S, Garner CD, Wang CY, Linsmaier-Bednar EM, King CM: Activation of N-hydroxyphenacetin to mutagenic and nucleic acid-binding metabolites by acyltransfer, deacylation and sulfate conjugation. Cancer Res (41): 3424–3429, 1981.PubMedGoogle Scholar
  29. 29.
    Wirth PJ, Dybing E, von Bahr C, Thorgeirsson SS: Mechanism of N-hydroxyacetylarylamine mutagenicity in the Salmonella test-system. Metabolic activation of N-hydroxyphenacetin by liver and kidney fractions from rat, mouse, hamster and man. Mol Pharmacol (18): 117–127, 1980.PubMedGoogle Scholar
  30. 30.
    Carpenter HM, Mudge GH: Acetaminophen nephrotoxicity: Studies on renal acetylation and deacetylation. J Pharmacol Exp Ther (218): 171–167, 1981.Google Scholar
  31. 31.
    Newton JF, Yoshimoto M, Bernstein J, Rush GF, Hook JB: Acetaminophen nephrotoxicity in the rat. II. Strain differences in nephrotoxicity and metabolism of p-aminophenol, a metabolite of acetaminophen. Toxicol Appl Pharmacol (69): 307–318, 1983.PubMedCrossRefGoogle Scholar
  32. 32.
    Zenser TV. Mattammal MB, Davis BB: Differential distribution of mixed function oxidase activities in rabbit kidney. J Pharmacol Exp Ther (207): 719–725, 1978.PubMedGoogle Scholar
  33. 33.
    Cavallo T: Fine structural localization of endogenous peroxidase activity in inner medullary interstitial cells of the rat kidney. Lab Invest (31): 458–464, 1974.PubMedGoogle Scholar
  34. 34.
    Smith WL, Wilkin GP: Immunochemistry of prostaglandin endoperoxide forming cyclooxygenases: The detection of the cyclooxygenases in rat, rabbit and guinea pig kidneys by immunofluorescence. Prostaglandins (13): 873–892, 1977.PubMedCrossRefGoogle Scholar
  35. 35.
    Samuelsson B, Goldyne M, Granström E, Hamberg M, Hammar-ström S, Malmsten C: Prostaglandins and thromboxanes. Ann Rev Biochem (47): 997–1029, 1978.PubMedCrossRefGoogle Scholar
  36. 36.
    Miyamoto T, Ogino N, Yamamoto S, Hayaishi O: Purification of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes. J Biol Chem (251): 2629–2636, 1976.PubMedGoogle Scholar
  37. 37.
    O’Brien PJ, Rahimtula A: The possible involvement of a peroxidase in prostaglandin biosynthesis. Biochem Biophys Res Commun (70): 832–838, 1976.PubMedCrossRefGoogle Scholar
  38. 38.
    Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature (New Biol) (231): 232–235, 1971.Google Scholar
  39. 39.
    Marnett LJ: Polycyclic aromatic hydrocarbon oxidation during prostaglandin biosynthesis. Life Sci (29): 531–546, 1981.PubMedCrossRefGoogle Scholar
  40. 40.
    Marnett LJ, Eling TE: Cooxidation during prostaglandin biosynthesis: A pathway for the metabolic activation of xenobiotics. In: Hodgson E, Bend JR, Philpot RM (ed) Reviews in Biochemical Toxicology 5. Elsevier Biomedical. New York, 1983, pp 135–172.Google Scholar
  41. 41.
    Eling T, Boyd J, Reed G, Mason R, Sivarajah K: Xenobiotic metabolism by prostaglandin endoperoxide synthetase. Drug Metab Rev (14): 219–248, 1983.CrossRefGoogle Scholar
  42. 42.
    Moldéus P, Rahimtula A: Metabolism of paracetamol to a glutathione conjugate catalyzed by prostaglandin synthetase. Biochem Biophys Res Commun (96): 469–475, 1980.PubMedCrossRefGoogle Scholar
  43. 43.
    Mohandas J, Duggin GG, Horvath JS, Tiller DJ: Metabolic oxidation of acetaminophen (paracetamol) mediated by cytochrome P-450 mixed-function oxidase and prostaglandin endoperoxide synthetase in rabbit kidney. Toxicol Appl Pharmacol (61): 252–259, 1981.PubMedCrossRefGoogle Scholar
  44. 44.
    Boyd JA, Eling TE: Prostaglandin endoperoxide synthetasedependent cooxidation of acetaminophen to intermediates which covalently bind in vitro to rabbit renal medullary microsomes. J Pharmacol Exp Ther (219): 659–664, 1981.PubMedGoogle Scholar
  45. 45.
    Moldéus P, Andersson B, Rahimtula A, Berggren M: Prostaglandin synthetase catalyzed activation of paracetamol. Biochem Pharmacol (31): 1363–1368, 1982.PubMedCrossRefGoogle Scholar
  46. 46.
    Egan RW, Gale PH, Kuehl Jr FA: Reduction of hydroperoxides in the prostaglandin biosynthetic pathway by a microsomal peroxidase. J Biol Chem (254): 3295–3302, 1979.PubMedGoogle Scholar
  47. 47.
    Zenser TV, Mattammal MB, Herman CA, Joshi S, Davis BB: Effect of acetaminophen on prostaglandin E2 and prostaglandin F2a synthesis in the renal inner medulla of rat. Biochim Biophys Acta (542): 486–495, 1978.PubMedGoogle Scholar
  48. 48.
    Egan RW, Paxton J, Kuehl Jr FA: Mechanism for irreversible self-deactivation of prostaglandin synthetase. J Biol Chem (251): 7329–7335, 1976.PubMedGoogle Scholar
  49. 49.
    Jollow DJ, Thorgeirsson SS, Potter WZ, Hashimoto M, Mitchell JR: Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and non-toxic doses of acetaminophen. Pharmacology (12): 251–271, 1974.PubMedCrossRefGoogle Scholar
  50. 50.
    Hinson JA, Pohl LR, Monks TJ, Gillette JR: Acetaminophen-induced hepatotoxicity. Life Sci (29): 107–116, 1981.PubMedCrossRefGoogle Scholar
  51. 51.
    Corcoran GB, Mitchell JR, Vaishnav YN, Horning EC: Evidence that acetaminophen and N-hydroxyacetaminophen form a common arylating intermediate, N-acetyl-p-benzoquinone-imine. Mol Pharmacol (18): 536–542, 1980.PubMedGoogle Scholar
  52. 52.
    Nelson SD, Dahlin DC, Rauchman EJ, Rosen GM: Peroxidasemediated formation of reactive metabolites of acetaminophen. Mol Pharmacol (20): 195–199, 1981.PubMedGoogle Scholar
  53. 53.
    Ohnishi T, Yamazaki H, Iyanagi T, Nakamura T, Yamasaki I: One-electron-transfer reactions in biological systems. II. The reaction of free radicals formed in the enzymatic oxidation. Biochim Biophys Acta (172): 357–369, 1969.PubMedCrossRefGoogle Scholar
  54. 54.
    deVries J: Hepatotoxic metabolic activation of paracetamol and its derivatives phenacetin and benorilate: oxygenation or electron transfer? Biochem Pharmacol (30): 399–402, 1981.CrossRefGoogle Scholar
  55. 55.
    Duggin GG, Mudge GH: Analgesic nephropathy: Renal distribution of acetaminophen and its conjugates. J Pharmacol Exp Ther (199): 1–9, 1976.PubMedGoogle Scholar
  56. 56.
    Andersson B, Nordenskjöld M, Rahimtula A, Moldéus P: Prostaglandin synthetase-catalyzed activation of phenacetin metabolites to genotoxic products. Mol Pharmacol (22): 479–485, 1982.PubMedGoogle Scholar
  57. 57.
    Josephy PD, Eling TE, Mason RP: An electron spin resonance study of the activation of benzidine by peroxidases. Mol Pharmacol (23): 766–770, 1983.PubMedGoogle Scholar
  58. 58.
    Andersson B, Larsson R, Rahimtula A, Moldéus P: Hydroperoxide-dependent activation of p-phenetidine catalyzed by prostaglandin synthase and other peroxidases. Biochem Pharmacol (32): 1045–1050, 1983.PubMedCrossRefGoogle Scholar
  59. 59.
    Andersson B, Larsson R, Rahimtula A, Moldéus P: Prostaglandin synthase and horseradish peroxidase catalyzed DNA-binding of p-phenetidine. Carcinogenesis (5): 161–165, 1984.PubMedCrossRefGoogle Scholar
  60. 60.
    Baud L, Nivez M-P, Chansel D, Ardaillou R: Stimulation by oxygen radicals of prostaglandin production by rat renal glomeruli. Kidney Int (20): 332–339, 1981.PubMedCrossRefGoogle Scholar
  61. 61.
    Griffin BW, Ting PL: Mechanism of N-demethylation of aminopyrene by hydrogen peroxide catalyzed by horseradish peroxide, metmyoglobin and protohemin. Biochemistry (17): 2206–2211, 1978.PubMedCrossRefGoogle Scholar
  62. 62.
    Harnett LJ, Siedlik PH, Fung LWM: Oxidation of phenidene and BW 755 C by prostaglandin endoperoxide synthetase. J Biol Chem (257): 6957–6964, 1982.Google Scholar
  63. 63.
    Josephy PD, Eling T, Mason RP: An electron spin resonance study of the activation of benzidine by peroxidases. Mol Pharmacol (23): 766–770, 1983.PubMedGoogle Scholar
  64. 64.
    Josephy PD, Eling T, Mason RP: The horseradish peroxidase catalyzed oxidation of 3,5,3’,5’-tetramethylbenzidine:free radical and charge transfer complex intermediates. J Biol Chem (257): 3669–3675, 1982.PubMedGoogle Scholar
  65. 65.
    Josephy PD, Eling T, Mason RP: Cooxidation of the clinical reagent 3,5,3’,5’-tetramethylbenzidine by prostaglandin synthase. Cancer Res (42): 2567–2570, 1982.PubMedGoogle Scholar
  66. 66.
    Ross D, Larsson R, Andersson B, Nilsson U, Lindqvist T, Lindeke B, Moldéus P: The oxidation of p-phenetidine by horse radish peroxidase and prostaglandin synthase and the fate of glutathione during such reactions. Biochem Pharmacol, In press, 1984/1985.Google Scholar
  67. 67.
    Moldéus P, O’Brien PJ, Thor H, Berggren M, Orrenius S: Oxidation of glutathione by free radical intermediates formed during peroxidase-catalyzed N-demethylation reactions. FEBS Lett (162): 411–415, 1983.Google Scholar
  68. 68.
    Moldéus P, Jernström B: Interaction of glutathione with reactive intermediates. In: Larsson A, Orrenius S, Holmgren A, Mannervik B (eds). Functions of glutathione. Biochemical, Physiological Toxicological and Clinical Aspects. Raven Press, New York, 1983, pp 99–108.Google Scholar
  69. 69.
    Schafer K, Bonfacic M, Bahnemann D, Asmus KO: Addition of oxygen to organic sulfur radicals. J Phys Chem (82): 2777–2780, 1978.CrossRefGoogle Scholar
  70. 70.
    Quintilliani M, Badiello R, Tamba M, Esfandi A, Gorin G: Radiolysis of glutathione in oxygen-containing solutions of pH 7. Int J Radiat Biol (32): 195–202, 1977.CrossRefGoogle Scholar
  71. 71.
    Quintilliani M, Badiello R, Tamba M, Gorin G: Radiation chemical basis for the role of glutathione in cellular radiation sensitivity. In: Modification of radiosensitivity of biological systems. Vienna IAEA, 1976, pp 2937Google Scholar
  72. 72.
    Saunders BC: Peroxidases and catalases. In: Eichhorn GL (ed). Inorganic Biochemistry 2. Elsevier, New York, 1973, pp 988–1021.Google Scholar
  73. 73.
    Parker VD: Anodic oxidation of amines. In: Baizer MM (ed). Organic electrochemistry. Marcel-Dekker Inc., New York, 1973, pp 509–529.Google Scholar
  74. 74.
    Larsson R, Ross D, Rahimtula A, Norbeck K, Lindeke B. Moldéus P: Reactive products formed by peroxidase catalyzed oxidation of p-phenetidine. Chem Biol Interactions, In press, 1984.Google Scholar
  75. 75.
    Ross D, Larsson R, Norbeck K, Ryhage R, Moldéus P: Characterization and mechanism of formation of reactive products formed during peroxidase catalyzed oxidation of p-phenetidine: trapping of reactive species using reduced glutathione and butylated hydroxyanisole. Molec Pharmacol, In press, 1984.Google Scholar
  76. 76.
    Claiborne A, Fridovich I: Chemical and enzymatic intermediates in the peroxidation of o-dianisidine by horseradish peroxidase. I. Spectral properties of the products of dianisidine oxidation. Biochemistry (18): 2324–2329, 1979.PubMedCrossRefGoogle Scholar
  77. 77.
    Oldfield LF, Bockris JO’M: Reversible oxidation-reduction reactions of aromatic amines. J Phys Colloid Chem (55): 1255–1274, 1951.CrossRefGoogle Scholar
  78. 78.
    Josephy PD, Van Dame A: Reaction of 4-substituted phenols with benzidine in a peroxidase system. Biochem Pharmacol, submitted, 1983.Google Scholar
  79. 79.
    Larsson R, Andersson B, von Bahr C, Berlin T, Moldéus P: Prostaglandin synthase catalyzed metabolic activation of p-phenetidine in the human kidney medulla. Biochem Pharmacol, submitted, 1983.Google Scholar
  80. 80.
    Saker BM, Kincaid-Smith P: Papillary necrosis in experimental analgesic nephropathy. Brit Med J (1): 161–162, 1969.PubMedCrossRefGoogle Scholar

Copyright information

© Martinus Nijhoff Publishing, Boston 1985

Authors and Affiliations

  • Peter Moldéus
  • Roger Larsson
  • David Ross

There are no affiliations available

Personalised recommendations