Clinical Pharmacokinetics

, Volume 31, Issue 3, pp 215–230 | Cite as

Idiosyncratic Drug Reactions

Metabolic Bioactivation as a Pathogenic Mechanism


The metabolism of drugs to chemically reactive metabolites may play a pivotal role in the pathogenesis of idiosyncratic drug toxicity. A large number of in vitro studies and a limited number of in vivo studies have demonstrated that many drugs are not toxic per se, but produce toxicity after undergoing enzyme-mediated bioactivation to chemically reactive species. Such reactive species may inflict a toxic insult on the cell either directly or indirectly by acting as a hapten and initiating an immune-mediated reaction.

The enzymes responsible for bioactivation have been widely studied, both quantitatively and qualitatively, the most important being the enzymes of the cytochrome P450 (CYP) mixed function oxidase system. CYP enzymes are the most predominant drug metabolising enzymes in the liver and are also present in most other tissues of the body. The diversity of this enzyme system means that a wide range of xenobiotic substrates can be bioactivated by either a single CYP isoform or multiple isoforms of this enzyme superfamily. Other enzymes do, however, play an important role in drug bioactivation. In white blood cells, for example, myeloperoxidase has been shown to bioactivate a wide range of drugs.

In other tissues low in CYP activity, prostaglandin H synthase may also be responsible for bioactivation; e.g. in the kidney paracetamol (acetaminophen) toxicity is thought to result from activation via this enzyme. The phase II or conjugation enzymes may also be important in the ultimate bioactivation of drug molecules. Whilst activation by these enzymes is, to date, apparently confined to chemicals, most drugs are also substrates for these enzymes and bioactivation by them must remain a possibility.


Clozapine Dapsone Tacrine Methoxyflurane Reactive Metabolite 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, editors. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977: 44Google Scholar
  2. 2.
    Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34: 377–95PubMedGoogle Scholar
  3. 3.
    Park BK, Kitteringham NR. Adverse drug reactions and drug metabolism. Adverse Drug React Bull 1987; 122: 456–9Google Scholar
  4. 4.
    Woolf TF, Jordan RA. Basic concepts in drug metabolism: part 1. J Clin Pharmacol 1987; 27: 15–7PubMedGoogle Scholar
  5. 5.
    Tephly TR, Burchell B. UDP-glucuronyl transferases: a family of detoxifying enzymes. Trends Pharmacol Sci 1990; 11: 276–29PubMedGoogle Scholar
  6. 6.
    Pirmohamed M, Kitteringham NR, Park BK. The role of active metabolites in drug toxicity. Drug Saf 1994; 11: 114–44PubMedGoogle Scholar
  7. 7.
    Park BK, Pirmohamed M, Kitteringham NR. The role of cytochrome P450 enzymes in hepatic and extrahepatic human drug toxicity. Pharmacol Ther 1995; 68: 385–424PubMedGoogle Scholar
  8. 8.
    Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54: 17–61PubMedGoogle Scholar
  9. 9.
    Juchau MR, Lee QP, Fantel AG. Xenobiotic biotransformation/bioactivation in organogenesis-stage conceptal issues: implications for embryotoxicity and teratogenesis. Drug Metab Rev 1992; 24: 195–238PubMedGoogle Scholar
  10. 10.
    Park BK, Coleman JW, Kitteringham NR. Drug disposition and drug hypersensitivity. Biochem Pharmacol 1987; 36: 581–90PubMedGoogle Scholar
  11. 11.
    Pohl LR, Satoh H, Christ DD, et al. Immunologic and metabolic basis of drug hypersensitivities. Annu Rev Pharmacol 1988; 28: 367–87Google Scholar
  12. 12.
    Gillette JR, Lau SS, Monks TJ. Intra- and extra-cellular formation of metabolites from chemically reactive species. Biochem Soc Trans 1984; 12: 4–7PubMedGoogle Scholar
  13. 13.
    Boelsterli UA. Specific targets of covalent drug-protein interactions in hepatocytes and their toxicological significance in drug-induced liver injury. Drug Metab Rev 1993; 25: 395–451PubMedGoogle Scholar
  14. 14.
    Pessayre D, Larrey D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988; 2: 385–423PubMedGoogle Scholar
  15. 15.
    Gonzalez FJ, Jaiswal AK, Nebert DW. P450 genes: evolution, regulation, and relationship to human cancer and pharmacogenetics. Cold Spring Harb Symp Quant Biol 1986; 51 Pt 2: 879–90Google Scholar
  16. 16.
    Gonzalez FJ. The molecular biology of cytochrome P450s. Pharmacol Rev 1989; 40: 243–88Google Scholar
  17. 17.
    Forrester LM, Henderson CJ, Glancey MJ, et al. Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs. Biochem J 1992; 281: 359–68PubMedGoogle Scholar
  18. 18.
    Nebert DW, Nelson DR, Adesnik M, et al. The P450 gene superfamily. Update on the naming of new genes and nomenclature of chromosomal loci. DNA 1989; 8: 1–13PubMedGoogle Scholar
  19. 19.
    Nebert DW, Nelson DR, Coon MJ, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 1991; 10: 1–14PubMedGoogle Scholar
  20. 20.
    Nelson DR, Koymans L, Kamataki T, et al. P450 superfamily: update of new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1–42PubMedGoogle Scholar
  21. 21.
    Murray BP, Edwards RJ, Murray S, et al. Human hepatic CYP1A1 and CYP1A2 content, determined with specific anti-peptide antibodies, correlates with the mutagenic activation of PhIP. Carcinogenesis 1993; 14: 585–92PubMedGoogle Scholar
  22. 22.
    Wong TK, Domin BA, Bent PE, et al. Correlation of placental microsomal activities with protein detected by antibodies to rabbit cytochrome-p-450 isozyme-6 in preparations from humans exposed to polychlorinated-biphenyls, quaterphenyls, and dibenzofurans. Cancer Res 1986; 46: 999–1004PubMedGoogle Scholar
  23. 23.
    Shimada T, Yun CH, Yamazaki H, et al. Characterization of human lung microsomal cytochrome-p-450 1a1 and its role in the oxidation of chemical carcinogens. Mol Pharmacol 1992; 41: 856–64PubMedGoogle Scholar
  24. 24.
    Crofts F, Cosma GN, Currie D, et al. A novel CYP1A1 gene polymorphism in African-Americans. Carcinogenesis 1993; 14: 1729–31PubMedGoogle Scholar
  25. 25.
    Nakachi K, Imai K, Hayashi S, et al. Polymorphisms of the CYP1A1 and glutathione-s-transferase genes associated with susceptibility to lung-cancer in relation to cigarette dose in a Japanese population. Cancer Res 1993; 53: 2994–9PubMedGoogle Scholar
  26. 26.
    Kadlubar FF. Biochemical individuality and its implications for drug and carcinogen metabolism: recent insights from acetyltransferase and cytochrome P4501A2 phenotyping and genotyping in humans. Drug Metab Rev 1994; 26: 37–46PubMedGoogle Scholar
  27. 27.
    Nakajima M, Yokoi T, Mizutani M, et al. Phenotyping of CYP1A2 in japanese population by analysis of caffeine urinary metabolites — absence of mutation prescribing the phenotype in the CYP1A2 gene. Cancer Epidemiol Biomarkers Prev 1994; 3: 413–21PubMedGoogle Scholar
  28. 28.
    Edwards RJ, Murray BP, Murray S, et al. Contribution of CYP1A1, and CYP1A2 to the activation of heterocyclic amines in monkeys and human. Carcinogenesis 1994; 15: 829–36PubMedGoogle Scholar
  29. 29.
    Park BK, Madden S, Spaldin V, et al. Tacrine transaminitis: potential mechanisms. Alz Dis Assoc Disord 1994; 8: S39–49Google Scholar
  30. 30.
    Woolf TF, Pool WF, Walker RM, et al. Liver reactions to tacrine. In: Cameron RG, Feuer G, de la Iglesia FA, editors. Drug-induced hepatotoxicity. Berlin: Springer-Verlag, 1996: 395–410Google Scholar
  31. 31.
    Madden S, Woolf TF, Pool WF, et al. An investigation into the formation of stable, protein-reactive and cytotoxic metabolites from tacrine in vitro: studies with human and rat liver microsomes. Biochem Pharmacol 1993; 46: 13–20PubMedGoogle Scholar
  32. 32.
    Spaldin V, Madden S, Pool WF, et al. The effect of enzyme-inhibition on the metabolism and activation of tacrine by human liver-microsomes. Br J Clin Pharmacol 1994; 38: 15–22PubMedGoogle Scholar
  33. 33.
    Spaldin V, Madden S, Adams DA, et al. Determination of human hepatic cytochrome P4501A2 activity in-vitro: use of tacrine as an isoenzyme-specific probe. Drug Metab Dispos 1995; 23: 929–34PubMedGoogle Scholar
  34. 34.
    Madden S, Spaldin V, Hayes RN, et al. Species variation in the bioactivation of tacrine by hepatic microsomes. Xenobiotica 1995; 25: 103–16PubMedGoogle Scholar
  35. 35.
    Madden S, Spaldin V, Park BK. Clinical pharmacokinetics of tacrine. Clin Pharmacokinet 1995; 28: 449–57PubMedGoogle Scholar
  36. 36.
    Dahl M-L, Llerena A, Bondesson U, et al. Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. Br J Clin Pharmacol 1994; 37: 71–4PubMedGoogle Scholar
  37. 37.
    Pirmohamed M, Williams D, Madden S, et al. Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Ther 1995; 272: 984–90PubMedGoogle Scholar
  38. 38.
    Gonzalez FJ. Human cytochromes P450: problems and prospects. Trends Pharmacol Sci 1992; 13: 346–52PubMedGoogle Scholar
  39. 39.
    Goldstein JA, de Morais SMF. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 1994; 4: 285–300PubMedGoogle Scholar
  40. 40.
    Page MA, Boutagy JS, Shenfield GM. A screening test for slow metabolizers of tolbutamide. Br J Clin Pharmacol 1991; 31: 649–54PubMedGoogle Scholar
  41. 41.
    Dansette PM, Amar C, Valadon P, et al. Hydroxylation and formation of electrophilic metabolites of tienilic acid and its isomer by human liver microsomes. Biochem Pharmacol 1991; 41: 553–60PubMedGoogle Scholar
  42. 42.
    Homberg JC, Andre C, Abuaf N. A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis. Clin Exp Immunol 1984; 55: 561–70PubMedGoogle Scholar
  43. 43.
    Beaune PH, Bourdi M. Autoantibodies against cytochrome P-450 in drug-induced autoimmune hepatitis. Ann NY Acad Sci 1993; 685: 641–5PubMedGoogle Scholar
  44. 44.
    Beaune P, Dansette PM, Mansuy D, et al. Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. Proc Natl Acad Sci USA 1987; 84: 551–5PubMedGoogle Scholar
  45. 45.
    Mansuy D, Valadon P, Erdelmeier I, et al. Thiophene S-oxides as new reactive metabolites: formation by cytochrome P450 dependent oxidation and reaction with nucleophiles. J Am Chem Soc 1991; 113: 7825–6Google Scholar
  46. 46.
    Smith GH. Treatment of infections in the patient with acquired immunodeficiency syndrome. Arch Intern Med 1994; 154: 949–73PubMedGoogle Scholar
  47. 47.
    Koopmans PP, Vanderven AJAM, Vree TB, et al. Pathogenesis of hypersensitivity reactions to drugs in patients with HIV-infection: allergic or toxic. AIDS 1995; 9: 217–22PubMedGoogle Scholar
  48. 48.
    Bayard PJ, Berger TG, Jacobson MA. Drug hypersensitivity reactions and human immunodeficiency virus disease. J Acquir Immune Defic Syndr 1992; 5: 1237–57PubMedGoogle Scholar
  49. 49.
    van der Ven AJ, Koopmans PP, Vree TB, et al. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; II: 431–3Google Scholar
  50. 50.
    Cribb AE, Spielberg SP, Griffin GP. N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502C subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes. Drug Metab Dispos 1995; 23: 406–14PubMedGoogle Scholar
  51. 51.
    Hertl M, Jugert F, Merk HF. Cd8(+) dermal t-cells from a sulfamethoxazole-induced bullous exanthem proliferate in response to drug-modified liver-microsomes. Br J Dermatol 1995; 132: 215–20PubMedGoogle Scholar
  52. 52.
    Carr A, Vasak E, Munro V, et al. Immunohistological assessment of cutaneous drug hypersensitivity in patients with HIV-infection. Clin Exp Immunol 1994; 97: 260–5PubMedGoogle Scholar
  53. 53.
    Carr A, Tindall B, Penny R, et al. In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV. Clin Exp Immunol 1993; 94: 21–5PubMedGoogle Scholar
  54. 54.
    Rieder MJ, Uetrecht JP, Shear NH, et al. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9PubMedGoogle Scholar
  55. 55.
    Vanderven AJM, Koopmans PP, Vree TB, et al. Drug intolerance in HIV disease. J Antimicrob Chemother 1994; 34: 1–5Google Scholar
  56. 56.
    Roederer M, Staal FJT, Osada H, et al. CD4 and CD8 T cells with high intracellular glutathione levels are selectively lost as the HIV infection progresses. Int Immunol 1991; 3: 933–7PubMedGoogle Scholar
  57. 57.
    Buhl R, Holroyd KJ, Mastrangeli A, et al. Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet 1989; II: 1294–8Google Scholar
  58. 58.
    Pirmohamed M, Williams D, Tingle MD, et al. Intracellular glutathione in the peripheral blood cells of HIV-infected patients: failure to show a deficiency. AIDS 1996; 10: 501–7PubMedGoogle Scholar
  59. 59.
    Aukrust P, Svardal AM, Muller F, et al. Increased levels of oxidized glutathione in CD4+ lymphocytes associated with disturbed intracellular redox balance in human immunodeficiency virus type 1 infection. Blood 1995; 86: 258–67PubMedGoogle Scholar
  60. 60.
    Riley RJ, Cribb AE, Spielberg SP Glutathione transferase u deficiency is not a marker for predisposition to sulphonamide toxicity. Biochem Pharmacol 1991; 42: 696–8PubMedGoogle Scholar
  61. 61.
    Coleman MD, Scott AK, Breckenridge AM, et al. The use of cimetidine as a selective inhibitor of dapsone N-hydroxylation in man. Br J Clin Pharmacol 1990; 30: 761–7PubMedGoogle Scholar
  62. 62.
    Rhodes LE, Tingle MD, Park BK, et al. Cimetidine improves the therapeutic toxic ratio of dapsone in patients on chronic dapsone therapy. Br J Dermatol 1995; 132: 257–62PubMedGoogle Scholar
  63. 63.
    Gonzalez F, Meyer UA. Molecular genetics of the debrisoquin-sparteine polymorphism. Clin Pharmacol Ther 1991; 50: 233–8PubMedGoogle Scholar
  64. 64.
    Daly AK, Cholerton S, Gregory W, et al. Metabolic polymorphisms. Pharmacol Ther 1993; 57: 129–60PubMedGoogle Scholar
  65. 65.
    Koymans LMH, Donne-Op den Kelder GM, Koppele TE, et al. Cytochromes P450: their active-site structure and mechanism of oxidation. Drug Metab Rev 1993; 25: 325–87PubMedGoogle Scholar
  66. 66.
    Penman BW, Reece J, Smith T, et al. Characterization of a human cell-line expressing high-levels of CDNA-derived CYP2D6. Pharmacogenetics 1993; 3: 28–39PubMedGoogle Scholar
  67. 67.
    Guengerich FP, Turvy CG. Comparison of levels of several human cytochrome P450 microsomal enzymes and epoxide hydrolase in normal and disease states using immunochemical analysis of surgical liver samples. J Pharmacol Exp Ther 1990; 256: 1189–94Google Scholar
  68. 68.
    Hayashi S, Watanabe J, Kawajiri K. Genetic polymorphisms in the 5′-flanking region change transcriptional regulation of the human cytochrome P450IIE1gene. J Biochem Tokyo 1991; 110: 559–65PubMedGoogle Scholar
  69. 69.
    Day CP, Bassendine MF. Genetic predisposition to alcoholic liver disease. Gut 1992; 33: 1444–7PubMedGoogle Scholar
  70. 70.
    Tuma DJ, Klassen LW. Immune responses to acetaldehyde-protein adducts: role in alcoholic liver disease. Gastroenterology 1992; 103: 1969–73PubMedGoogle Scholar
  71. 71.
    Moncada C, Torres V, Varghese G, et al. Ethanol-derived immunoreactive species formed by free radical mechanisms. Mol Pharmacol 1994; 46: 786–91PubMedGoogle Scholar
  72. 72.
    Clot P, Bellomo G, Tabone M, et al. Detection of antibodies against proteins modified by hydroxyethyl free-radicals in patients with alcoholic cirrhosis. Gastroenterology 1995; 108: 201–7PubMedGoogle Scholar
  73. 73.
    Pirmohamed M, Kitteringham NR, Quest LJ, et al. Genetic polymorphism of cytochrome P4502E1 and risk of alcoholic liver disease in Caucasians. Pharmacogenetics 1995; 5: 351–7PubMedGoogle Scholar
  74. 74.
    Tsutsumi M, Takada A, Wang JS. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver-disease. Gastroenterology 1994; 107: 1430–5PubMedGoogle Scholar
  75. 75.
    Carr LG, Hartleroad JY, Liang YB, et al. Polymorphism at the P450IIE1 locus is anot associated with alcoholic liver disease in Caucasian men. Alcohol Clin Exp Res 1994; 19: 182–4Google Scholar
  76. 76.
    Maezawa Y, Yamauchi M, Toda G. Association between restriction fragment length polymorphism of the human cytochrome P450IIE1 gene and susceptibility to alcoholic liver cirrhosis. Am J Gastroenterol 1994; 89: 561–5PubMedGoogle Scholar
  77. 77.
    Kharasch ED, Thummel KE, Mautz D, et al. Clinical enflurane metabolism by cytochrome P4502E1. Clin Pharmacol Ther 1994; 55: 434–40PubMedGoogle Scholar
  78. 78.
    Pohl LR, Kenna JG, Satoh H, et al. Neoantigens associated with halothane hepatitis. Drug Metab Rev 1989; 20: 203–17PubMedGoogle Scholar
  79. 79.
    Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis 1990; 10: 305–15PubMedGoogle Scholar
  80. 80.
    National Halothane Study. Summary of the national halothane study. JAMA 1966; 197: 121–34Google Scholar
  81. 81.
    Gut J, Christen U, Huwyler J. Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993; 58: 133–55PubMedGoogle Scholar
  82. 82.
    Kenna JG, Neuberger J, Williams R. Evidence for expression in human liver of halothane-induced neoantigens recognized by antibodies in sera from patients with halothane hepatitis. Hepatology 1988; 8: 1635–41PubMedGoogle Scholar
  83. 83.
    Park BK, Kitteringham NR. Effects of fluorine substitution on drug-metabolism: pharmacological and toxicological implications. Drug Metab Rev 1994; 26: 605–43PubMedGoogle Scholar
  84. 84.
    Kharasch ED, Thummel KE. Identification of cytochrome P450 2E1 as the predominant enzyme catalysing human liver microsomal defluorination of sevoflurane, isoflurane and methoxyfluorane. Anesthesiology 1993; 79: 795–807PubMedGoogle Scholar
  85. 85.
    Mazze RI, Cousins MJ. Renal toxicity of anaesthetics: with specific reference to the nephrotoxicity of methoxyflurane. Can Anaesth Soc J 1973; 20: 64–80PubMedGoogle Scholar
  86. 86.
    Roman RJ, Carter JR, North WC, et al. Renal tubular site of action of fluoride in Fischer 344 rats. Anesthesiology 1977; 46: 260–4PubMedGoogle Scholar
  87. 87.
    Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536–42PubMedGoogle Scholar
  88. 88.
    Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anaesthesia in volunteers. Anesthesiology 1977; 46: 265–71PubMedGoogle Scholar
  89. 89.
    Eger EI, Smuckler EA, Ferrell LD, et al. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21–30PubMedGoogle Scholar
  90. 90.
    Frink EJ. The hepatic-effects of sevoflurane. Anesth Analg 1995; 81: S46–50PubMedGoogle Scholar
  91. 91.
    Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995; 82: 689–99PubMedGoogle Scholar
  92. 92.
    Pirmohamed M, Kitteringham NR, Breckenridge AM, et al. The effect of enzyme induction on the cytochrome P450-mediated bioactivation of carbamazepine by mouse liver microsomes. Biochem Pharmacol 1992; 44: 2307–14PubMedGoogle Scholar
  93. 93.
    Crill WE. Drugs 5 years later: carbamazepine. Ann Intern Med 1973; 79: 844–7PubMedGoogle Scholar
  94. 94.
    Shear NH, Spielberg SP, Cannon M, et al. Anticonvulsant hypersensitivity syndrome: in vitro risk assessment. J Clin Invest 1988; 82: 1826–32PubMedGoogle Scholar
  95. 95.
    Pirmohamed M, Kitteringham NR, Guenthner TM, et al. Investigation into the formation of cytotoxic, protein reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol 1992; 43: 1675–82PubMedGoogle Scholar
  96. 96.
    Pirmohamed M, Graham A, Roberts P, et al. Carbamazepine hypersensitivity: assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine. Br J Clin Pharmacol 1991; 32: 741–9PubMedGoogle Scholar
  97. 97.
    Tybring G, von Bahr C, Bertilsson L, et al. Metabolism of carbamazepine and its epoxide metabolite in human and rat liver in vitro. Drug Metab Dispos 1981; 9: 561–4PubMedGoogle Scholar
  98. 98.
    Kroetz DL, Kerr BM, McFarland LV, et al. Measurement of in vivo microsomal epoxide hydrolase activity in white subjects. Clin Pharmacol Ther 1993; 53: 306–15PubMedGoogle Scholar
  99. 99.
    Madden S, Maggs JL, Kitteringham NR, et al. Bioactivation of carbamazepine in the rat in vivo. Br J Clin Pharmacol 1996; 41: 464PGoogle Scholar
  100. 100.
    Lertratanangkoon K, Horning MG. Metabolism of carbamazepine. Drug Metab Dispos 1982; 10: 1–10PubMedGoogle Scholar
  101. 101.
    Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism: role of CYP3A4 and CYP2C8 in 10,11-epoxide formation. Biochem Pharmacol 1994; 47: 1969–79PubMedGoogle Scholar
  102. 102.
    Bernus I, Dickinson RG, Hooper WD, et al. Early-stage autoinduction of carbamazepine metabolism in humans. Eur J Clin Pharmacol 1994; 47: 355–60PubMedGoogle Scholar
  103. 103.
    Gaedigk A, Spielberg SP, Grant DM. Characterization of the microsomal epoxide hydrolase gene in patients with anticonvulsant adverse drug reactions. Pharmacogenetics 1994; 4: 142–53PubMedGoogle Scholar
  104. 104.
    Green VJ, Pirmohamed M, Kitteringham NR, et al. Genetic analysis of microsomal epoxide hydrolase in patients with carbamazepine hypersensitivity. Biochem Pharmacol 1995; 50: 1353–9PubMedGoogle Scholar
  105. 105.
    Lillibridge JH, Amore BM, Slattery JT, et al. Protein-reactive metabolites of carbamazepine in mouse liver microsomes. Drug Metab Dispos 1996; 24: 509–14PubMedGoogle Scholar
  106. 106.
    Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10: 267–78PubMedGoogle Scholar
  107. 107.
    Pumford NR, Martin BM, Hinson JA. A metabolite of acetaminophen covalently binds to the 56kDa selenium binding protein. Biochem Biophys Res Commun 1992; 182: 1348–53PubMedGoogle Scholar
  108. 108.
    Raucy JL, Lasker JM, Lieber CS, et al. Acetaminophen activation by human liver cytochromes P-450IIE1 and P-450IA2. Arch Biochem Biophys 1989; 271: 270–83PubMedGoogle Scholar
  109. 109.
    Thummel KE, Lee CA, Kunze KL, et al. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 1993; 45: 1563–9PubMedGoogle Scholar
  110. 110.
    Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure. Ann Intern Med 1986; 104: 399–404PubMedGoogle Scholar
  111. 111.
    Bray GP, Harrison PM, O’Grady JG, et al. Long-term anticonvulsant therapy worsens outcome in paracetamol-induced fulminant hepatic failure. Hum Exp Toxicol 1992; 11: 265–70PubMedGoogle Scholar
  112. 112.
    Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995; 22: 767–73PubMedGoogle Scholar
  113. 113.
    Grossman SJ, Jollow DJ. Role of dapsone hydroxylamine in dapsone induced hemolytic anemia. J Pharmacol Exp Ther 1988; 244: 118–25PubMedGoogle Scholar
  114. 114.
    Zuidema J, Hilbers-Moddermann ESM, Merkus FWHM. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet 1986; 11: 299–315PubMedGoogle Scholar
  115. 115.
    Coleman MD, Breckenridge AM, Park BK. Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes. Br J Clin Pharmacol 1989; 28: 389–95PubMedGoogle Scholar
  116. 116.
    Uetrecht J, Zahid N, Shear NH, et al. Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells. J Pharmacol Exp Ther 1988; 245: 274–9PubMedGoogle Scholar
  117. 117.
    Kramer PA, Glader BE, Li TK. Mechanism of methaemoglobin formation by diphenylsulfones. Effect of 4-amino-4′-hydroxy-aminodiphenylsulfone and other p-substituted derivatives. Biochem Pharmacol 1972; 21: 1265–74PubMedGoogle Scholar
  118. 118.
    Park BK, Pirmohamed M, Tingle MD, et al. Bioactivation and bioinactivation of drugs and drug metabolites: relevance to adverse drug reactions. Toxicol In Vitro 1994; 8: 613–21PubMedGoogle Scholar
  119. 119.
    Gill HJ, Tingle MD, Park BK. N-hydroxylation of dapsone by multiple enzymes of cytochrome P450: implications for inhibition of haemotoxicity. Br J Clin Pharmacol 1995; 40: 531–9PubMedGoogle Scholar
  120. 120.
    Fleming CM, Branch RA, Wilkinson GR, et al. Human liver microsomal N-hydroxylation of dapsone by cytochrome P-4503A4. Mol Pharmacol 1992; 41: 975–80PubMedGoogle Scholar
  121. 121.
    Mitra AK, Thummel KE, Kalhorn TF, et al. Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo. Clin Pharmacol Ther 1995; 58: 556–66PubMedGoogle Scholar
  122. 122.
    Coleman MD, Rhodes LE, Scott AK, et al. The use of cimetidine to reduce dose-dependent methaemoglobinaemia in dermatitis hepertiformis patients. Br J Clin Pharmacol 1992; 34: 244–9PubMedGoogle Scholar
  123. 123.
    Gometz JL, Dupont A, Casen L, et al. Incidence of liver toxicity associated with the use of flutamide in prostatic cancer patients. Am J Med 1992; 92: 465–70Google Scholar
  124. 124.
    Corkery JC, Bihrle I, McCaffrey JA, et al. Flutamide-related fulminant hepatic failure. J Clin Gastroenterol 1991; 13: 364PubMedGoogle Scholar
  125. 125.
    Hart W, Stricker BHC. Flutamide and hepatitis. Ann Intern Med 1989; 110: 943–4PubMedGoogle Scholar
  126. 126.
    Moller S, Iverson P, Franzman MB. Flutamide-induced liver failure. J Hepatol 1990; 10: 346–9PubMedGoogle Scholar
  127. 127.
    Berson A, Wolf C, Chacaty C, et al. Metabolic activation of the nitroaromatic antiandrogen flutamide by rat and human cytochromes P-450, including forms belonging to the 3A and 1A subfamilies. J Pharmacol Exp Ther 1993; 265: 366–72PubMedGoogle Scholar
  128. 128.
    Burchell B, Nebert DW, Nelson DR, et al. The UDP glucuronosyl-transferase gene superfamily: suggested nomenclature based on evolutionary divergence. DNA Cell Biol 1991; 10: 487–94PubMedGoogle Scholar
  129. 129.
    Tephly TR, Townsend M, Green MD. UDP-glucuronosyl-transferases in the metabolic disposition of xenobiotics. Drug Metab Rev 1989; 20: 689–95PubMedGoogle Scholar
  130. 130.
    Spahn-Langguth H, Benêt LZ. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as detoxification mechanism. Drug Metab Rev 1992; 24: 5–47PubMedGoogle Scholar
  131. 131.
    Kroemer HK, Klotz U. Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 1992; 23: 292–310PubMedGoogle Scholar
  132. 132.
    Smith PC, McDonagh AF, Benet LZ. Irreversible binding of zomepirac to plasma protein in vitro and in vivo. J Clin Invest 1986; 77: 934–9PubMedGoogle Scholar
  133. 133.
    Pumford NR, Myers TG, Davila JC, et al. Immunochemical detection of liver protein adducts of the nonsteroidal anti-inflammatory drug diclofenac. Chem Res Toxicol 1993; 6: 147–50PubMedGoogle Scholar
  134. 134.
    Kretz-Rommel A, Boelsterli UA. Cytotoxic activity of T cells and non-T cells from diclofenac-immunized mice against cultured syngeneic hepatocytes exposed to diclofenac. Hepatology 1995; 22: 213–22PubMedGoogle Scholar
  135. 135.
    Banks AT, Zimmerman HJ, Ishak KG, et al. Diclofenac-associated hepatotoxicity: analysis of 180 cases reported to the Food and Drug Administration as adverse reactions. Hepatology 1995; 22: 820–7PubMedGoogle Scholar
  136. 136.
    Boyer TD. The glutathione-S-transferases: an update. Hepatology 1989; 9: 486–96PubMedGoogle Scholar
  137. 137.
    van Bladeren PJ. Formation of toxic metabolites from drugs and other xenobiotics by glutathione conjugation. Trends Pharmacol Sci 1988; 9: 295–9PubMedGoogle Scholar
  138. 138.
    Guenthner TM, Kuk J, Nguyen M, et al. Epoxide hydrolases: immunochemical detection in human tissues. In: Jeffrey EH, editors. Human drug metabolism: from molecular biology to man. Boca Raton: CRC Press, 1993: 65–80Google Scholar
  139. 139.
    Skoda RC, Demierre A, McBride OW, et al. Human microsomal xenobiotic epoxide hydrolase. Complementary DNA sequence, complementary DNA-directed expression in COS-1 cells, and chromosomal localization. J Biol Chem 1988; 263: 1549–54PubMedGoogle Scholar
  140. 140.
    Uetrecht JP. Mechanism of hypersensitivity reactions: proposed involvement of reactive metabolites generated by activated leukocytes. Trends Pharmacol Sci 1989; 10: 463–7PubMedGoogle Scholar
  141. 141.
    Uetrecht JP. The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. Drug Metab Rev 1992; 24: 299–366PubMedGoogle Scholar
  142. 142.
    Fischer V, Haar JA, Greiner L, et al. Possible role of free radical formation in clozapine (Clozaril)-induced agranulocytosis. Mol Pharmacol 1991; 40: 846–53PubMedGoogle Scholar
  143. 143.
    Maggs JL, Williams D, Pirmohamed M, et al. The metabolic formation of reactive intermediates from clozapine: a drug associated with agranulocytosis in man. J Pharmacol Exp Ther 1995; 275: 1463–75PubMedGoogle Scholar
  144. 144.
    Liu ZC, Uetrecht JP. Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to cells. J Pharmacol Exp Ther 1995; 275: 1476–83PubMedGoogle Scholar
  145. 145.
    Furst SM, Uetrecht JP. Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. Biochem Pharmacol 1993; 45: 1267–75PubMedGoogle Scholar
  146. 146.
    Eling TE, Thompson DC, Foureman GL, et al. Prostaglandin-h synthase and xenobiotic oxidation. Annu Rev Pharmacol Toxicol 1990; 30: 1–45PubMedGoogle Scholar
  147. 147.
    Moldeus P, Rahimtula A. Metabolism of paracetamol to a glutathione conjugate catalysed by prostaglandin synthetase. Biochem Biophys Res Commun 1980; 96: 469–75PubMedGoogle Scholar
  148. 148.
    Potter DW, Hinson JA. The 1-electron and 2-electron oxidation of acetaminophen catalyzed by prostaglandin-H synthase. J Biol Chem 1987; 262: 974–80PubMedGoogle Scholar
  149. 149.
    West PR, Harman LS, Josephy PD, et al. Acetaminophen: enzymatic formation of a transient phenoxyl free-radical. Biochem Pharmacol 1984; 33: 2933–6PubMedGoogle Scholar
  150. 150.
    Boyd JA, Eling TE. Prostaglandin endoperoxide synthetase-dependent co-oxidation of acetaminophen to intermediates which covalently bind in vitro to rabbit renal medullary microsomes. J Pharmacol Exp Ther 1981; 219: 659–64PubMedGoogle Scholar
  151. 151.
    O’Neill PM, Harrison AC, Storr RC, et al. The effect of fluorine substitution on the metabolism and antimalarial activity of amodiaquine. J Med Chem 1994; 37: 1362–70PubMedGoogle Scholar
  152. 152.
    Tingle MD, Jewell H, Maggs JL, et al. The bioactivation of amodiaquine by human polymorphonuclear leukocytes invitro: chemical mechanisms and the effects of fluorine substitution. Biochem Pharmacol 1995; 50: 1113–9PubMedGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  • Munir Pirmohamed
    • 1
  • Stephen Madden
    • 1
  • B. Kevin Park
    • 1
  1. 1.Department of Pharmacology and TherapeuticsThe University of LiverpoolLiverpoolEngland

Personalised recommendations