Drug Safety

, Volume 11, Issue 2, pp 114–144 | Cite as

The Role of Active Metabolites in Drug Toxicity

  • Munir Pirmohamed
  • Neil R. Kitteringham
  • B. Kevin Park
Review Article Drug Safety Concepts


Adverse drug reactions can be caused by the parent drug or a metabolite of that drug. The metabolite may be stable or chemically reactive, the resultant toxicity being either a direct extension of the pharmacology of the drug, or unrelated to the known pharmacology of the drug and dependent on the chemical properties of the compound. Many different organ systems may be affected, and there are several mechanisms involved in determining organ-specific, and sometimes cell-selective, toxicity. An imbalance between bioactivation of a drug to a toxic metabolite and its detoxification is of prime importance in determining individual susceptibility. Such an imbalance may be genetically determined or acquired and, furthermore, may be systemic or tissue-specific. Prevention of metabolite-mediated toxicity is possible once the mechanism of toxicity has been elucidated.


Adis International Limited Halothane Zidovudine MPTP Terfenadine 
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.


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  1. 1.
    Committee on Safety of Medicines. CSM update. BMJ 1985; 291: 46CrossRefGoogle Scholar
  2. 2.
    Woolf TF, Jordan RA. Basic concepts in drug metabolism: part I. J Clin Pharmacol 1987; 27: 15–7PubMedCrossRefGoogle Scholar
  3. 3.
    Park BK. Metabolic basis of adverse drug reactions. J R Coll Physicians Lond 1986; 20: 195–200PubMedGoogle Scholar
  4. 4.
    Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34: 377–95PubMedCrossRefGoogle Scholar
  5. 5.
    Williams RT. The metabolism of foreign compounds and the detoxication mechanisms. In: Williams RT, editor. Detoxication mechanisms. New York: John Wiley, 1959: 717–40Google Scholar
  6. 6.
    Tephly TR, Burchell B. UDP-glucuronyl transferases: a family of detoxifying enzymes. Trends Pharmacol Sci 1990; 11: 276–9PubMedCrossRefGoogle Scholar
  7. 7.
    Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977: 44Google Scholar
  8. 8.
    Grahame-Smith DG, Aronson JK, editors. Oxford textbook of clinical pharmacology and drug therapy. Oxford: Oxford University Press, 1992Google Scholar
  9. 9.
    Watkins PB. Role of cytochrome P450 in drug metabolism and hepatotoxicity. Semin Liver Dis 1990; 10: 235–50PubMedCrossRefGoogle Scholar
  10. 10.
    Williams AT, Burk RF. Carbon tetrachloride hepatotoxicity: an example of free radical-mediated injury. Semin Liver Dis 1990; 10: 279–84PubMedCrossRefGoogle Scholar
  11. 11.
    Park BK, Coleman JW, Kitteringham NR. Drug disposition and drug hypersensitivity. Biochem Pharmacol 1987; 36: 581–90PubMedCrossRefGoogle Scholar
  12. 12.
    Pohl RL, Satoh H, Christ DD, et al. Immunologic and metabolic basis of drug hypersensitivities. Annu Rev Pharmacol 1988; 28: 367–87CrossRefGoogle Scholar
  13. 13.
    Coombes RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, editor. Clinical aspects of immunology. Oxford: Oxford University Press, 1968: 575–96Google Scholar
  14. 14.
    Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54: 17–61PubMedCrossRefGoogle Scholar
  15. 15.
    Juchau MR. Bioactivation in chemical teratogenesis. Annu Rev Pharmacol Toxicol 1989; 29: 165–87PubMedCrossRefGoogle Scholar
  16. 16.
    Pirmohamed M, Kitteringham NR, Park BK. Idiosyncratic reactions to antidepressants: a review of possible mechanisms and predisposing factors. Pharmacol Ther 1992; 53: 105–25PubMedCrossRefGoogle Scholar
  17. 17.
    Strieker BHC, Spoelstra P, editors. Drug-induced hepatic injury: a comprehensive survey of the literature on adverse drug reactions up to January 1985. Amsterdam: Elsevier, 1985Google Scholar
  18. 18.
    Zimmerman HJ, editor. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century Crofts, 1978Google Scholar
  19. 19.
    Davis M, Williams R. Hepatic disorders. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1991: 245–304Google Scholar
  20. 20.
    Neuberger JM. Halothane and hepatitis. incidence, predisposing factors and exposure guidelines. Drug Saf 1990; 5: 28–38Google Scholar
  21. 21.
    Bray GP. Liver failure induced by paracetamol. BMJ 1993; 306: 157–8PubMedCrossRefGoogle Scholar
  22. 22.
    Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10: 267–78PubMedCrossRefGoogle Scholar
  23. 23.
    Raucy JL, Lasker JM, Lieber CS, et al. Acetaminophen activation by human liver cytochromes P-450IIE1 and P-450IA2. Arch Biochem Biophys 1989; 271: 270–83PubMedCrossRefGoogle Scholar
  24. 24.
    Thummel KE, Lee CA, Kunze KL, et al. Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4. Biochem Pharmacol 1993; 45: 1563–9PubMedCrossRefGoogle Scholar
  25. 25.
    Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management. Drugs 1983; 25: 290–314PubMedCrossRefGoogle Scholar
  26. 26.
    Jollow DJ, Mitchell JR, Potter WZ, et al. Acetaminophen-induced hepatic necrosis, II: role of covalent binding in vivo. J Pharmacol Exper Ther 1973; 187: 195–202Google Scholar
  27. 27.
    Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis, I: role of drug metabolism. J Pharmacol Exp Ther 1973; 187: 185–94PubMedGoogle Scholar
  28. 28.
    Myers LL, Bierschmitt WP, Khairallah EA, et al. Acetaminophen-induced inhibition of hepatic mitochondrial respiration of mice. Toxicol Appl Pharmacol 1988; 93: 378–87CrossRefGoogle Scholar
  29. 29.
    Potter WZ, Davis DC, Mitchell JR, et al. Acetaminophen-induced hepatic necrosis, III: cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 1973; 187: 203–10PubMedGoogle Scholar
  30. 30.
    Tirmenstein MA, Nelson SD. Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regeoisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 1989; 264: 9814–9PubMedGoogle Scholar
  31. 31.
    Tirmenstein MA, Nelson SD. Acetaminophen-induced oxidation of protein thiols: contribution of impaired thiol metabolizing enzymes and the breakdown of adenine nucleotides. J Biol Chem 1990; 265: 3059–65PubMedGoogle Scholar
  32. 32.
    Powis G, Svingen BA, Dahlin DC, et al. Enzymatic and non-enzymatic reduction of N-acetyl-p-benzoquinoneimine and some properties of the N-acetyl-p-benzoquinoneimine radical. Biochem Pharmacol 1984; 33: 2367–70PubMedCrossRefGoogle Scholar
  33. 33.
    Rosen GM, Singletary WVJ, Rauckman EJ, et al. Acetaminophen hepatotoxicity. An alternative mechanism. Biochem Pharmacol 1983; 32: 2053–9Google Scholar
  34. 34.
    Corcoran GB, Bauer JA, Lau TWD. Immediate rise in intracellular calcium and glycogen phosphorylase a activities upon acetaminophen covalent binding leading to hepatotoxicity in mice. Toxicology 1988; 50: 157–67PubMedCrossRefGoogle Scholar
  35. 35.
    Tsokos-Kuhn JO, Hughes H, Smith CV, et al. Alkylation of the liver plasma membrane and inhibition of the Ca2+-ATPase by acetaminophen. Biochem Pharmacol 1988; 37: 2125–31PubMedCrossRefGoogle Scholar
  36. 36.
    Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29: 1153–7PubMedCrossRefGoogle Scholar
  37. 37.
    Lieber CS. Biochemical and molecular basis of alcohol induced injury to liver and other tissues. N Engl J Med 1988; 319: 1639–50PubMedCrossRefGoogle Scholar
  38. 38.
    Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986; 104: 399–404PubMedGoogle Scholar
  39. 39.
    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: 265–70PubMedCrossRefGoogle Scholar
  40. 40.
    De Morais SMF, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology 1992; 102: 577–86PubMedGoogle Scholar
  41. 41.
    Lieh-Lai MW, Sarnaik AP, Newton JF, et al. Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. J Pediatr 1984; 105: 125–8PubMedCrossRefGoogle Scholar
  42. 42.
    Meredith TJ, Prescott LF, Vale JF. Why do patients still die from paracetamol poisoning? BMJ 1986; 293: 345–6PubMedCrossRefGoogle Scholar
  43. 43.
    Harrison PM, Keays R, Bray GP, et al. Improved outcome of paracetamol induced hepatic failure by late administration of acetylcysteine. Lancet 1990; 335: 1572–3PubMedCrossRefGoogle Scholar
  44. 44.
    Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303: 1026–9PubMedCrossRefGoogle Scholar
  45. 45.
    Albano E, Rundgren M, Harvison PJ, et al. Mechanism of N-acetyl-p-benzoquinoneimine cytotoxicity. Mol Pharmacol 1985; 28: 306–11PubMedGoogle Scholar
  46. 46.
    Birge RB, Bartolone JB, McCann DJ, et al. Selective protein arylation by acetaminophen and 2,6-dimethyl acetaminophen in cultured hepatocytes from phenobarbital-induced and uninduced mice. Biochem Pharmacol 1989; 38: 4429–38PubMedCrossRefGoogle Scholar
  47. 47.
    Harmon AW. The effectiveness of antioxidants in reducing paracetamol-induced damage subsequent to paracetamol activation. Res Commun Chem Pathol Pharmacol 1985; 49: 215–28Google Scholar
  48. 48.
    Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology. 1987; 37: 379–85PubMedCrossRefGoogle Scholar
  49. 49.
    Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities — II: US experience since 1984. Neurology. 1989; 39: 201–7PubMedCrossRefGoogle Scholar
  50. 50.
    Scheffner D, Konig St, Rauterberg-Ruland I, et al. Fatal liver failure in 16 children with valproate therapy. Epilepsia 1988; 29: 530–42PubMedCrossRefGoogle Scholar
  51. 51.
    Kassahun K, Farrell K, Abbott F. Identification and characterisation of the glutathione and N-acetylcysteine conjugates of (E)-2-propyl-2,4-pentadienoic acid, a toxic metabolite of valproic acid, in rats and humans. J Pharmacol Exper Ther 1991; 19: 525–35Google Scholar
  52. 52.
    Rettenmeier AW, Prickett AS, Gordon WP, et al. Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid: evidence for the formation of chemically reactive intermediates. Drug Metab Dispos 1985; 13: 81–96PubMedGoogle Scholar
  53. 53.
    Rettie AE, Rettenmeier AW, Howald WN, et al. Cytochrome P450-catalyzed formation of VPA, a toxic metabolite of valproic acid. Science 1987; 235: 890–3PubMedCrossRefGoogle Scholar
  54. 54.
    National Halothane Study. Summary of the National Halothane Study. JAMA 1966; 197: 121–34CrossRefGoogle Scholar
  55. 55.
    Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis 1990; 10: 305–15PubMedCrossRefGoogle Scholar
  56. 56.
    Pohl LR, Kenna JG, Satoh H, et al. Neoantigens associated with halothane hepatitis. Drug Metab Rev 1989; 20: 203–17PubMedCrossRefGoogle Scholar
  57. 57.
    Neuberger J, Kenna JG. Halothane hepatitis: a model of immune mediated drug hepatotoxicity. Clin Sci 1987; 72: 263–70PubMedGoogle Scholar
  58. 58.
    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: 1635–41PubMedCrossRefGoogle Scholar
  59. 59.
    Gut J, Christen U, Huwyler J. Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993; 58: 133–55PubMedCrossRefGoogle Scholar
  60. 60.
    Christ DD, Kenna JG, Kammerer W, et al. Enflurane metabolism produces covalently bound liver adducts recognised by antibodies from patients with halothane hepatitis. Anesthesiology 1988; 69: 833–8PubMedCrossRefGoogle Scholar
  61. 61.
    Arria AM, Tarter RE, Van-Thiel DH. Vulnerability to alcoholic liver disease. Recent Dev Alcohol 1991; 9: 185–204PubMedGoogle Scholar
  62. 62.
    Day CP, Bassendine MF. Genetic predisposition to alcoholic liver disease. Gut 1992; 33: 1444–7PubMedCrossRefGoogle Scholar
  63. 63.
    Tuma DJ, Klassen LW. Immune responses to acetaldehyde-protein adducts: role in alcoholic liver disease. Gastroenterology 1992; 103: 1969–73PubMedGoogle Scholar
  64. 64.
    Zetterman RK. Autoimmunity and alcoholic liver disease. Am J Med 1990; 89: 127–8PubMedCrossRefGoogle Scholar
  65. 65.
    Sorrell MF, Leevy CM. Lymphocyte transformation and alcohol liver injury. Gastroenterology 1972; 63: 1020–5PubMedGoogle Scholar
  66. 66.
    Laskin CA, Vidins E, Blendis LM, et al. Autoantibodies in alcoholic liver disease. Am J Med 1990; 89: 129–33PubMedCrossRefGoogle Scholar
  67. 67.
    Niemela O, Klajner F, Orrego H, et al. Antibodies against acetaldehyde-modified protein epitopes in human alcoholics. Hepatology 1987; 7: 1210–4PubMedCrossRefGoogle Scholar
  68. 68.
    Niemela O, Juvonen T, Parkkila S. Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest 1991; 87: 1367–74PubMedCrossRefGoogle Scholar
  69. 69.
    Worrall S, De-Jersey J, Shanley BC, et al. Antibodies against acetaldehyde-modified epitopes: presence in alcoholic, nonalcoholic liver disease and control subjects. Alcohol Alcohol 1990; 25: 509–17PubMedGoogle Scholar
  70. 70.
    Bickers DR. Xenobiotic metabolism in the skin. In: Goldsmith LA, editor. Physiology, biochemistry and molecular biology of the skin, Vol. 2. Oxford: Oxford University Press, 1991: 1480–501Google Scholar
  71. 71.
    Kao J, Carver MP. Cutaneous metabolism of xenobiotics. Drug Metab Rev 1990; 22: 363–410PubMedCrossRefGoogle Scholar
  72. 72.
    Mukhtar H, Khan WA. Cutaneous cytochrome P-450. rug Metab Rev 1989; 20: 657–73CrossRefGoogle Scholar
  73. 73.
    Murray GI, Barnes TS, Sewell HF, et al. The immunohistochemical localisation and distribution of cytochrome P-450 in normal human hepatic and extrahepatic tissues with a monoclonal antibody to human cytochrome P-450. Br J Clin Pharmacol 1988; 25: 465–75PubMedCrossRefGoogle Scholar
  74. 74.
    van Pelt FNAM, Olde Meierink YJM, Blaauboer BJ, et al. Immunohistochemical detection of cytochrome P450 isoenzymes in cultured human epidermal cells. J Histochem Cytochem 1990; 38: 1847–51PubMedCrossRefGoogle Scholar
  75. 75.
    Kao J. Estimating the contribution by skin to systemic metabolism. Ann NY Acad Sci 1988; 548: 90–6PubMedCrossRefGoogle Scholar
  76. 76.
    Longley BJ, Braverman IM, Edelson RL. Immunology and the skin. Current concepts. Ann NY Acad Sci 1988; 548: 225–32PubMedCrossRefGoogle Scholar
  77. 77.
    Raviglione MC, Pablos-Mendez A, Battan R. Clinical features and management of severe dermatological reactions to drugs. Drug Saf 1990; 5: 39–64PubMedCrossRefGoogle Scholar
  78. 78.
    Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis: a population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990; 126: 43–7PubMedCrossRefGoogle Scholar
  79. 79.
    Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400PubMedCrossRefGoogle Scholar
  80. 80.
    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: 741–9PubMedCrossRefGoogle Scholar
  81. 81.
    Shear NH, Spielberg SP, Cannon M, et al. Anticonvulsant hypersensitivity syndrome: in vitro risk assessment. J Clin Invest 1988; 82: 1826–32PubMedCrossRefGoogle Scholar
  82. 82.
    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: 1675–82PubMedCrossRefGoogle Scholar
  83. 83.
    Spielberg SP, Gordon GB, Blake DA, et al. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981; 305: 722–7PubMedCrossRefGoogle Scholar
  84. 84.
    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: 2307–14PubMedCrossRefGoogle Scholar
  85. 85.
    Riley RJ, Lambert C, Maggs JL, et al. An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil, and mianserin. Br J Clin Pharmacol 1988; 26: 577–88PubMedCrossRefGoogle Scholar
  86. 86.
    Riley RJ, Kitteringham NR, Park BK. Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro. Br J Clin Pharmacol 1989; 28: 482–7PubMedCrossRefGoogle Scholar
  87. 87.
    Spielberg SP. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc 1984; 43: 2308–13PubMedGoogle Scholar
  88. 88.
    Spielberg SP. Acetaminophen toxicity in human lymphocytes in vitro. J Pharmacol Exp Ther 1980; 213: 395–8PubMedGoogle Scholar
  89. 89.
    Reider MJ, Uetrecht JP, Shear NH, et al. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro ‘rechallenge’ with hydroxylamine metabolites. Ann Intern Med 1989; 110: 286–9Google Scholar
  90. 90.
    Shear NH, Spielberg SP. In vitro evaluation of a toxic metabolite of sulfadiazine. Can J Physiol Pharmacol 1985; 63: 1370–2PubMedCrossRefGoogle Scholar
  91. 91.
    Cribb AE, Miller M, Leeder JS, et al. Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Drug Metab Dispos 1991; 19: 900–6PubMedGoogle Scholar
  92. 92.
    van der Ven AJ, Koopmans PP, Vree TB, et al. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; 2: 1991Google Scholar
  93. 93.
    Hein DW, Weber WW. Metabolism of procainamide, hydralazine, and isoniazid in relation to autoimmune (-like) reactions. In: Kammuller ME, et al., editors. Autoimmunity and toxicology: immune disregulation induced by drugs and chemicals. Amsterdam: Elsevier, 1989: 239–65Google Scholar
  94. 94.
    Batchelor JR, Welsh Kl, Tinoco RM, et al. Hydralazine-induced systemic lupus erythematosus: influence of HLA-DR and sex on susceptibility. Lancet 1980; 1: 1107–9PubMedCrossRefGoogle Scholar
  95. 95.
    Russell GI, Bing RF, Jones JAG, et al. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. QJ Med 1987; 65: 845–52Google Scholar
  96. 96.
    Woosley RL, Drayer DE, Reidenberg MM, et al. Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome. N Engl J Med 1978; 298: 1157–9PubMedCrossRefGoogle Scholar
  97. 97.
    Lahita R, Kluger J, Drayer DE, et al. Antibodies to nuclear antigens in patients treated with procainamide or acetylprocainamide. N Engl J Med 1979; 301: 1382–5PubMedCrossRefGoogle Scholar
  98. 98.
    Roden DM, Reele SB, Higgins SB, et al. Antiarrythmic efficacy, pharmacokinetics, and safety of N-acetylprocainamide in human subjects: comparisons with procainamide. Am J Cardiol 1980; 46: 463–8PubMedCrossRefGoogle Scholar
  99. 99.
    Claas FHJ. Drug-induced immune granulocytopenia. Baillieres Clin Immunol Allergy 1987; 1: 357–67Google Scholar
  100. 100.
    Pisciotta AV. Drug-induced agranulocytosis: peripheral destruction of polymorphonuclear leukocytes and their marrow precursors. Blood Rev 1990; 4: 226–37PubMedCrossRefGoogle Scholar
  101. 101.
    Vincent PC. Drug-induced aplastic anaemia and agranulocytosis: incidence and mechanisms. Drugs 1986; 31: 52–63PubMedCrossRefGoogle Scholar
  102. 102.
    Cribb AE, Miller M, Tesoro A, et al. Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils form humans and dogs. Mol Pharmacol 1990; 38: 744–51PubMedGoogle Scholar
  103. 103.
    Hurst JK, Barrette WC. Leukocytic oxygen activation and microbicidal oxidative toxins. Crit Rev Biochem Mol Biol 1989; 24: 271–328PubMedCrossRefGoogle Scholar
  104. 104.
    Fraiser LH, Kanekal S, Kehrer JP. Cyclophophamide toxicity. Characterising and avoiding the problem. Drugs 1991; 42: 781–95PubMedCrossRefGoogle Scholar
  105. 105.
    Kaufman DW, et al., editors. The drug etiology of agranulocytosis and anemia, New York: Oxford University Press, 1991Google Scholar
  106. 106.
    Gerson WT, Fine DG, Spielberg SP, et al. Anticonvulsant-induced aplastic anaemia: increased susceptibility to toxic drug metabolites in vitro. Blood 1983; 61: 889–93PubMedGoogle Scholar
  107. 107.
    Chaplin S. Bone marrow depression due to mianserin, phenylbutazone, oxyphenbutazone and chloramphenicol — part I. Adverse Drug React Acute Pois Rev 1986; 2: 97–136Google Scholar
  108. 108.
    Ichihara S, Tomisawa H, Fukazawa H, et al. Invovlement of leukocytes in the oxygenation and chlorination reaction of phenylbutazone. Biochem Pharmacol 1986; 35: 3935–9PubMedCrossRefGoogle Scholar
  109. 109.
    Yunis AA. Chloramphenicol toxicity? 25 years of research. Am J Med 1989; 87: 44–8Google Scholar
  110. 110.
    Yunis AA, Miller AM, Salem Z, et al. Nitrosochloramphenicol: possible mediator in chloramphenicol-nduced aplastic anemia. J Lab Clin Med 1980; 96: 36–46PubMedGoogle Scholar
  111. 111.
    Yunis AA. Chloramphenicol: relation of structure to activity and toxicity. Annu Rev Pharmacol Toxicol 1988; 28: 83–100PubMedCrossRefGoogle Scholar
  112. 112.
    Ascheri M, Eyer P, Kampffmeyer H. Formation and disposition of nitrosochloramphenicol in rat liver. Biochem Pharmacol 1985; 34: 3755–63CrossRefGoogle Scholar
  113. 113.
    Jimenez JJ, Isildar M, Yunis AA. Bone marrow damage induced by chlormphenicol may be mediated by its bacterial metabolites. Blood 1987; 70: 1180–5PubMedGoogle Scholar
  114. 114.
    Isildar M, Jimenez JJ, Arimura GK, et al. DNA damage in intact cells induced by bacterial metabolites of chloramphenicol. Am J Hematol 1988; 28: 40–6PubMedCrossRefGoogle Scholar
  115. 115.
    Isildar M, Abou-Khalil WH, Jimenez JJ, et al. Aerobic nitroreduction of dehydrochloramphenicol by human bone marrow. Toxicol Appl Pharmacol 1988; 94: 305–10PubMedCrossRefGoogle Scholar
  116. 116.
    Mullen CA, Kilstrup M, Blaese RM. Transfer of the bacterial gene for cytosine deaminase to mammalian cells confers lethal sensitivity to 5-fluorocytosine: a negative selection system. Proc Natl Acad Sci USA 1992; 89: 33–7PubMedCrossRefGoogle Scholar
  117. 117.
    Malet-Martino MC, Martino R, de Forni M, et al. Flucytosine conversion to fluorouracil in humans: does a correlation with gut flora exist? A report of two cases using fluorine-19 magnetic resonance spectroscopy. Infection 1991; 19: 178–80PubMedCrossRefGoogle Scholar
  118. 118.
    Harris BE, Diasio RB. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob Agents Chemother 1986; 29: 44–8PubMedCrossRefGoogle Scholar
  119. 119.
    Vialaneix JP, Malet-Martino MC, Hoffmann JS, et al. Direct detection of new flucytosine metabolites in human biofluids by 19F nuclear magentic resonance. Drug Metabol Dispos 1987; 15: 718–24Google Scholar
  120. 120.
    Perkocha LA, Rodgers GM. Hematologic aspects of human immunodeficiency virus infection: laboratory and clinical considerations. Am J Hematol 1988; 29: 94–105PubMedCrossRefGoogle Scholar
  121. 121.
    Zon LI, Arkin C, Groopman JE. Hematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol 1987; 66: 251–6PubMedCrossRefGoogle Scholar
  122. 122.
    McLeod GX, Hammer SM. Zidovudine: five years later. Ann Intern Med 1992; 117: 487–501PubMedGoogle Scholar
  123. 123.
    Boyar A, Beall G. HIV-seropositive thrombocytopenia: the action of zidovudine. AIDS 1991; 5: 1351–6PubMedCrossRefGoogle Scholar
  124. 124.
    Ballem PJ, Belzberg A, Devine DV, et al. Kinetic studies of the mechanism of thrombocytopenia in patients with human immunodeficiency virus infection. N Engl J Med 1992; 327: 1779–84PubMedCrossRefGoogle Scholar
  125. 125.
    Sommadossi JP, Carlisle R, Zhou Z. Cellular pharmacology of 3′-azido-3′-deoxythymidine with evidence of incorporation into DNA of human bone marrow cells. Mol Pharmacol 1989; 36: 9–14PubMedGoogle Scholar
  126. 126.
    Lutton JD, Mathew A, Levere RD, et al. Role of heme metabolism in AZT-induced bone marrow toxicity. Am J Hematol 1990; 35: 1–5PubMedCrossRefGoogle Scholar
  127. 127.
    Cretton EM, Placidi L, Sommadossi J-R Conversion of 3′-azido-3′-deoxythymidine (AZT) to its toxic metabolite, 3′-amino-3′-deoxythymidine (AMT) is mediated by cytochrome P450 and NADPH-cytochrome c reductase in liver microsomes. Clin Pharmacol Ther 1993; 53: 189Google Scholar
  128. 128.
    Cretton EM, Xie M-Y, Bevan RJ, et al. Catabolism of 3′-azido-3′-deoxythymidine in hepatocytes and liver microsomes, with eveidence of formation of 3′-amino-3′-deoxythymidine, a highly toxic catabolite for human bone marrow cells. Mol Pharmacol 1991; 39: 258–66PubMedGoogle Scholar
  129. 129.
    van der Wouw PA, van Leeuwen R, van Oers RH, et al. Effects of recombinant human granulocyte colony-stimulating factor on leucopenia in zidovudine-treated patients with AIDS and AIDS-related complex, a phase I/II study. Br J Haematol 1991; 78: 319–24PubMedCrossRefGoogle Scholar
  130. 130.
    Uetrecht J. Metabolism of drugs by activated leukocytes: implications for drug-induced lupus and other drug hypersensitivity reactions. Adv Exp Med Biol 1991; 283: 121–32PubMedCrossRefGoogle Scholar
  131. 131.
    Uetrecht JP. The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. Drug Metab Rev 1992; 24: 299–366PubMedCrossRefGoogle Scholar
  132. 132.
    Lieberman JA, Alvir JM. A report of clozapine-induced agranulocytosis in the United States. Incidence and risk factors. Drug Saf 1992; 7Suppl. 1: 1–2PubMedCrossRefGoogle Scholar
  133. 133.
    Safferman A, Lieberman JA, Kane JM, et al. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991; 17: 247–61PubMedGoogle Scholar
  134. 134.
    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
  135. 135.
    Jann MW. Clozapine. Pharmacotherapy 1991; 11: 179–95PubMedGoogle Scholar
  136. 136.
    Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med 1991; 324: 746–54PubMedCrossRefGoogle Scholar
  137. 137.
    Ammus S, Yunis AA. Drug-induced red cell dyscrasias. Blood Rev 1989; 3: 71–82PubMedCrossRefGoogle Scholar
  138. 138.
    Robicsek F. Acute methemoglobinemia during cardiopulmonary bypass caused by intravenous nitroglycerin infusion. J Thorac Cardiovasc Surg 1985; 90: 931–4PubMedGoogle Scholar
  139. 139.
    Coleman MD, Breckenridge AM, Park BK. Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes. Br J Clin Pharmacol 1989; 28: 389–95PubMedCrossRefGoogle Scholar
  140. 140.
    Grossman SJ, Jollow DJ. Role of dapsone hydroxylamine in dapsone induced hemolytic anemia. J Pharmacol Exp Ther 1988; 244: 118–25PubMedGoogle Scholar
  141. 141.
    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
  142. 142.
    Tingle MD, Coleman MD, Park BK. An investigation of the role of metabolism in dapsone-induced methaemoglobinaemia using a two compartment in vitro test system. Br J Clin Pharmacol 1990; 30: 829–38PubMedCrossRefGoogle Scholar
  143. 143.
    Coleman MD, Hoaksey PE, Breckenridge AM, et al. Inhibition of dapsone-induced methaemoglobinaemia in the isolated perfused rat liver. Br J Clin Pharmacol 1990; 29: 626PGoogle Scholar
  144. 144.
    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: 761–7PubMedCrossRefGoogle Scholar
  145. 145.
    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: 244–9PubMedCrossRefGoogle Scholar
  146. 146.
    Pounder RE, Craven ER, Henthorn JS, et al. Red cell abnormalities associated with sulphasalazine maintenance therapy for ulcerative colitis. Gut 1975; 16: 181–5PubMedCrossRefGoogle Scholar
  147. 147.
    Pirmohamed M, Coleman MD, Hussain F, et al. Direct and metabolism-dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes. Br J Clin Pharmacol 1991; 32: 303–10PubMedCrossRefGoogle Scholar
  148. 148.
    Pirmohamed M, Coleman MD, Galvani D, et al. Lack of interaction between sulphasalazine and cimetidine in patients with rheumatoid arthritis. Br J Rheumatol 1993; 32: 222–6PubMedCrossRefGoogle Scholar
  149. 149.
    Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. Pharmacol Ther 1990; 46: 377–94PubMedCrossRefGoogle Scholar
  150. 150.
    Timbrell JA. Principles of biochemical toxicology. London: Taylor and Francis, 1991Google Scholar
  151. 151.
    Brodie BB, Axelrod J. The fate of acetophenetidin and its metabolites in biological material. J Pharmacol Exp Ther 1949; 9: 58–67Google Scholar
  152. 152.
    Ayesh R, Smith RL. Genetic polymorphisms in human toxicology. In: Turner P, et al., editors. Recent advances in clinical pharmacology and toxicology. London: Churchill Livingstone, 1989: 137–57Google Scholar
  153. 153.
    Anonymous. Trouble with nomifensine. Drug Ther Bull 1985; 23: 98–100Google Scholar
  154. 154.
    Bournerias F, Habibi B. Nomifensine-induced immune haemolytic anaemia and impaired renal function. Lancet 1979; 2: 95–6PubMedCrossRefGoogle Scholar
  155. 155.
    Prescott LF, Illingworth RN, Critchley JAJH, et al. Acute haemolysis and renal failure after nomifensine overdosage. BMJ 1980; 281: 1392–3PubMedCrossRefGoogle Scholar
  156. 156.
    Salama A, Mueller-Eckhardt C. The role of metabolite-specific antibodies in nomifensine-dependent immune haemolytic anaemia. N Engl J Med 1985; 313: 469–74PubMedCrossRefGoogle Scholar
  157. 157.
    Weiss ME, Adkinson MF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40PubMedCrossRefGoogle Scholar
  158. 158.
    Page MI. The mechanisms of reaction of β-lactam antibiotics. Acc Chem Res 1984; 17: 144–51CrossRefGoogle Scholar
  159. 159.
    Levine BB. Immunochemical mechanisms involved in penicillin hypersensitivity in experimental animals and in human beings. Fed Proc 1965; 24: 45–50PubMedGoogle Scholar
  160. 160.
    Parker CW. Immunochemical mechanisms in penicillin allergy. Fed Proc 1965; 24: 51–4PubMedGoogle Scholar
  161. 161.
    Parker CW. Allergic reactions in man. Pharmacol Rev 1982; 34: 85–104PubMedGoogle Scholar
  162. 162.
    Spahn-Langguth H, Benet LZ. Acyl glucuronides revisited: is the glucuronidation process a toxification as well as detoxification mechanism. Drug Metab Rev 1992; 24: 5–47PubMedCrossRefGoogle Scholar
  163. 163.
    Smith PC, McDonagh AF, Benet LZ. Irreversible binding of zomepirac to plasma protein in vitro and in vivo. J Clin Invest 1986; 77: 934–9PubMedCrossRefGoogle Scholar
  164. 164.
    Murray MD, Brater DC. Renal toxicity of the nonsteroidal antiinflammatory drugs. Annu Rev Pharmacol Toxicol 1993; 32: 435–65CrossRefGoogle Scholar
  165. 165.
    Day RO, Graham GG, Williams KM, et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs. Pharmacol Ther 1987; 33: 383–433PubMedCrossRefGoogle Scholar
  166. 166.
    Pumford NR, Myers TG, Davila JC, et al. Immunochemical detection of liver protein adducts of the nonsteroidal antiinflammatory drug diclofenac. Chem Res Toxicol 1993; 6: 147–50PubMedCrossRefGoogle Scholar
  167. 167.
    Honig PK, Woosley RL, Zamani K, et al. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992; 52: 231–8PubMedCrossRefGoogle Scholar
  168. 168.
    MacConnell TJ, Stanners AJ. Torsades de pointes complicating treatment with terfenadine. BMJ 1991; 302: 1469PubMedCrossRefGoogle Scholar
  169. 169.
    Matthews DR, McNutt B, Okerholm R, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1991; 266: 2375–6CrossRefGoogle Scholar
  170. 170.
    Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90PubMedCrossRefGoogle Scholar
  171. 171.
    Garteiz DA, Hook RH, Walker BJ, et al. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung 1982; 32: 1185–90PubMedGoogle Scholar
  172. 172.
    Honig P, Wortham D, Zamani K, et al. Effect of erythromycin, clarithromycin and azithromycin on the pharmacokinetics of terfenadine. Clin Pharmacol Ther 1993; 53: 161CrossRefGoogle Scholar
  173. 173.
    Honig P, Wortham D, Zamani K, et al. The pharmacokinetics and cardiac consequences of the terfenadine-ketoconazole interaction. Clin Pharmacol Ther 1993; 53: 206CrossRefGoogle Scholar
  174. 174.
    Larrey D, Funck-Brentano C, Breil P. Effects of erythromycin on hepatic drug metabolising enzymes in humans. Biochem Pharmacol 1983; 32: 1063–8PubMedCrossRefGoogle Scholar
  175. 175.
    Larrey D, Tinel M, Pessayre D. Formation of inactive cytochrome P450 Fe (II)-metabolite complexes with several erythromycin derivatives but not with josamycin and midecamycin in rats. Biochem Pharmacol 1983; 32: 1487–93PubMedCrossRefGoogle Scholar
  176. 176.
    Sheets JJ, Mason JI. Ketoconazole: a potent inhibitor of cytochrome P-450 dependent drug metabolism in rat liver. Drug Metab Dispos 1984; 12: 603–8PubMedGoogle Scholar
  177. 177.
    Eller M, Stoltz M, Okerholm R, et al. Effect of hepatic disease on terfenadine and terfenadine metabolite pharmacokinetics. Clin Pharmacol Ther 1993; 53: 162Google Scholar
  178. 178.
    Russell T, Eller M, Hutcheson S, et al. Effect of renal disease on terfenadine metabolite pharmacokinetics. Clin Pharmacol Ther 1993; 53: 162Google Scholar
  179. 179.
    Chen Y, Gillis RA, Woosley RL. Block of delayed rectifier potassium current, Ik, by terfenadine in cat ventricular myocytes. J Am Coll Cardiol 1991; 17: 140AGoogle Scholar
  180. 180.
    Porembka DT, Lowder JN, Orlowski JP, et al. Etiology and management of doxorubicin cardiotoxicity. Crit Care Med 1989; 17: 569–72PubMedCrossRefGoogle Scholar
  181. 181.
    Lenaz LN, Page JA. Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 1976; 3: 111–20PubMedCrossRefGoogle Scholar
  182. 182.
    Anonymous. Childhood cancer, anthracyclines and the heart. Lancet 1992; 339: 1388–9CrossRefGoogle Scholar
  183. 183.
    Pratt CB, Ransom JL, Evans WE. Age-related adriamycin cardiotoxicity in children. Cancer Treat Rep 1978; 62: 1381–5PubMedGoogle Scholar
  184. 184.
    Von Hoff DD, Rozencweig M, Layard M, et al. Daunomycininduced cardiotoxicity in children and adults: a review of 110 cases. Am J Med 1977; 62: 200–8CrossRefGoogle Scholar
  185. 185.
    Doroshow JH, Locker GY, Baldinger J, et al. The effect of doxorubicin on hepatic and cardiac glutathione. Res Commun Chem Pathol Pharmacol 1979; 26: 285–95PubMedGoogle Scholar
  186. 186.
    Myers CE, McGuire WP, Liss RH, et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977; 197: 165–7PubMedCrossRefGoogle Scholar
  187. 187.
    Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 1990; 4: 3076–86PubMedGoogle Scholar
  188. 188.
    Olson RD, MacDonald JS, van Boxtel CJ, et al. Regulatory role of glutathione and soluble sulfhydryl groups in the toxicity of adriamycin. J Pharmacol Exp Ther 1980; 215: 450–4PubMedGoogle Scholar
  189. 189.
    Sinha BK, Politi PM. Anthracyclines. Canc Chemother Biol Response Modif 1990; 11: 45–57Google Scholar
  190. 190.
    Odom AL, Hatwig CA, Stanley JS, et al. Biochemical determinants of adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol 1992; 43: 831–6PubMedCrossRefGoogle Scholar
  191. 191.
    Legha SS, Benjamin RS, Makay B. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982; 96: 133–9PubMedGoogle Scholar
  192. 192.
    Green MD, Alderton P, Gross J, et al. Evidence of the selective alteration of anthracycline activity due to modulation by ICRF-187 (ADR-529). Pharmacol Ther 1990; 48: 61–9PubMedCrossRefGoogle Scholar
  193. 193.
    Devereux TR, Domin BA, Philpot RM. Xenobiotic metabolism by isolated pulmonary cells. Pharmacol Ther 1989; 41: 243–56PubMedCrossRefGoogle Scholar
  194. 194.
    Adesnik M, Atchison M. Genes for cytochrome P-450 and their regulation. CRC Crit Rev Biochem 1986; 19: 247–305PubMedCrossRefGoogle Scholar
  195. 195.
    Boyd MR. Biochemical mechanisms in chemical-induced lung injury: roles of metabolic activation. CRC Crit Rev Toxicol 1980; 7: 103–76CrossRefGoogle Scholar
  196. 196.
    Boyd MR. Evidence for the Clara cell as a site for cytochrome P450-dependent mixed-function oxidase activity in the lung. Nature 1977; 269: 713–5PubMedCrossRefGoogle Scholar
  197. 197.
    Guengerich FP, Shimada T. Human cytochrome P450 enzymes and chemical carcinogenesis. In: Jeffrey EH, editor. Human drug metabolism: from molecular biology to man. Boca Raton: CRC Press, 1993: 5–12Google Scholar
  198. 198.
    Buckpitt A, Buonarati M, Avey Bahnson L, et al. Relationship of cytochrome P450 activity to Clara cell cytotoxicity, II: comparison of stereoselectivity of naphthalene epoxidation in lung and nasal mucosa of mouse, hamster, rat and rhesus monkey. J Pharmacol Exp Ther 1992; 261: 364–72PubMedGoogle Scholar
  199. 199.
    Plopper CG, Suverkropp C, Morin D, et al. Relationship of cytochrome P-450 to Clara cell cytotoxicity, I: histopathologic comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene. J Pharmacol Exp Ther 1992; 261: 353–63PubMedGoogle Scholar
  200. 200.
    Jerina DM, Daly JW. Arene oxides: a new aspect of drug metabolism. Science 1974; 185: 573–82PubMedCrossRefGoogle Scholar
  201. 201.
    Kanekal S, Plopper C, Morin D, et al. Metabolism and cytotoxicity of naphthalene oxide in the isolated perfused mouse lung. J Pharmacol Exper Ther 1991; 256: 391–401Google Scholar
  202. 202.
    Buckpitt AR, Castagnoli N, Nelson SD, et al. Stereoselectivity of naphthalene epoxidation by mouse, rat, and hamster pulmonary, hepatic, and renal microsomal enzymes. Drug Metab Dispos 1987; 15: 491–8PubMedGoogle Scholar
  203. 203.
    Tingle MD, Pirmohamed M, Templeton E, et al. An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver in vitro. Biochem Pharmacol 1993; 46: 1529–38PubMedCrossRefGoogle Scholar
  204. 204.
    Smith LL. Mechanism of paraquat toxicity in lung and its relevance to treatment. Hum Toxicol 1987; 6: 31–6PubMedCrossRefGoogle Scholar
  205. 205.
    Gage JC. Action of paraquat and diquat on the respiration of liver cell fractions. Biochem J 1968; 109: 757–61PubMedGoogle Scholar
  206. 206.
    Rose MS, Smith LL, Wyatt I. The relevance of pentose phosphate pathway stimulation in rat lung to the mechanism of paraquat toxicity. Biochem Pharmacol 1976; 25: 1763–7PubMedCrossRefGoogle Scholar
  207. 207.
    Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990; 11: 1–20PubMedGoogle Scholar
  208. 208.
    Patel JM. Metabolism and pulmonary toxicity of cyclophosphamide. Pharmacol Ther 1990; 47: 137–46PubMedCrossRefGoogle Scholar
  209. 209.
    Smith RD, Kehrer JP. Cooxidation of cyclophosphamide as an alternative pathway for its bioactivation and lung toxicity. Cancer Res 1991; 51: 542–8PubMedGoogle Scholar
  210. 210.
    Sasame HA, Boyd MR. Superoxide and hydrogen peroxide production and NADPH oxidation stimulated by nitrofurantoin in lung microsomes: possible implications for toxicity. Life Sci 1979; 24: 1091–6PubMedCrossRefGoogle Scholar
  211. 211.
    Boyd MR, Stiko AW, Sasame HA. Metabolic activation of nitrofurantoin — possible implications for carcinogenesis. Biochem Pharmacol 1979; 28: 601–6PubMedCrossRefGoogle Scholar
  212. 212.
    Wang CY, Chiu CW, Bryan GT. Metabolism and disposition of N-(4-(-5-nitro-2-furyl)-(2-14C)-thiazolyl) acetamide in the rat. Drug Metabol Dispos 1975; 3: 89–95Google Scholar
  213. 213.
    Spielberg SP, Gordon GB. Nitrofurantoin cytotoxicity. In vitro assessment of risk based on glutathione metabolism. J Clin Invest 1981; 67: 37–41PubMedCrossRefGoogle Scholar
  214. 214.
    Calne DB, Langsten JW. Aetiology of Parkinson’s disease. Lancet 1983; 2: 1457–9PubMedCrossRefGoogle Scholar
  215. 215.
    Langston JW. MPTP and Parkinson’s disease. Trends Neurosci 1985; 8: 79–83CrossRefGoogle Scholar
  216. 216.
    Lewin R. Trail of ironies to Parkinson’s disease. Science 1984; 224: 1083–5PubMedCrossRefGoogle Scholar
  217. 217.
    Maret G, Testa B, Jenner P, et al. The MPTP story: MAO activates tetrahydropyridine derivatives ot toxins causing Parkinsonism. Drug Metab Rev 1990; 22: 291–332PubMedCrossRefGoogle Scholar
  218. 218.
    Marsden CD. Parkinson’s disease. Postgrad Med J 1992; 68: 538–43PubMedCrossRefGoogle Scholar
  219. 219.
    Chiba K, Trevor A, Castagnoli N. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 1984; 120: 574–8PubMedCrossRefGoogle Scholar
  220. 220.
    Javitch JA, D’Amato RJ, Strittmatter SM, et al. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 1985; 82: 2173–7PubMedCrossRefGoogle Scholar
  221. 221.
    D’Amato RJ, Alexander GM, Schwartzman RJ, et al. Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature 1987; 327: 324–6PubMedCrossRefGoogle Scholar
  222. 222.
    D’Amato RJ, Alexander GM, Schwartzman RJ, et al. Neuromelanin: a role in MPTP-induced neurotoxicity. Life Sci 1987; 40: 705–12PubMedCrossRefGoogle Scholar
  223. 223.
    D’Amato RJ, Benham DF, Snyder SH. Characterisation of the binding of N-methyl-4-phenylpyridine, the toxic metabolite of the parkinsonian neurotoxin N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine to neuromelanin. J Neurochem 1987; 48: 653–8PubMedCrossRefGoogle Scholar
  224. 224.
    Vyas I, Heikkila RE, Nicklas WJ. Studies on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Inhibition of NAD-linked substrate oxidation by its metabolite 1-methyl-4-phenylpyridinium. J Neurochem 1986; 46: 1501–7PubMedCrossRefGoogle Scholar
  225. 225.
    Rossetti ZL, Sotgiu A, Sharp D, et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and free radicals in vitro. Biochem Pharmacol 1988; 37: 4573–4PubMedCrossRefGoogle Scholar
  226. 226.
    The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–71CrossRefGoogle Scholar
  227. 227.
    The Parkinson Study Group. Effects of tocopherol and deprenylon the progression of disability in early Parkinson’s disease. N Engl J Med 1993; 328: 176–83CrossRefGoogle Scholar
  228. 228.
    Kofman OS. Deprenyl: protective vs. symptomatic effect. Can J Neurol Sci 1991; 18: 83–5PubMedGoogle Scholar
  229. 229.
    Kofman OS. Protective effect or symptomatic effect of deprenyl? N Engl J Med 1993; 328: 1715PubMedGoogle Scholar
  230. 230.
    Henderson CJ, Wolf CR. Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression. Biochem J 1991; 278: 499–503PubMedGoogle Scholar
  231. 231.
    Henderson CJ, Scott AA, Yang CS, et al. Testosterone-mediated regulation of cytochrome P450 gene expression will explain sex differences in response to nephrotoxins and carcinogens. Biochem J 1990; 266: 675–81PubMedGoogle Scholar
  232. 232.
    Wolf CR. Individuality in cytochrome P450 expression and its association with the nephrotoxic and carcinogenic effects of chemicals. IARC Sci Publ 1991; 281–7Google Scholar
  233. 233.
    Yaqoob M, Bell GM, Stevenson A, et al. Renal impairment with chronic hydrocarbon exposure. Q J Med 1993; 86: 165–74PubMedGoogle Scholar
  234. 234.
    Benitz KF, Diermeier HF. Renal toxicity of tetracycline degradation products. Proc Soc Exp Biol Med 1964; 115: 930–5PubMedGoogle Scholar
  235. 235.
    Lowe MB, Obst D, Tapp E. Renal damage caused by anhydro 4-EPI-tetracycline. Arch Pathol 1966; 81: 362–4PubMedGoogle Scholar
  236. 236.
    Toomath RJ, Morrison RB. Renal failure following methoxyflurane analgesia. NZ Med J 1987; 100: 707–8Google Scholar
  237. 237.
    Mazze RI, Shue GL, Jackson SH. Renal dysfunction associated with methoxyflurane anesthesia: a randomized, prospective clinical evaluation. JAMA 1971; 216: 278–80PubMedCrossRefGoogle Scholar
  238. 238.
    Samuelson PN, Merin RG, Taves DR, et al. Toxicity following methoxyflurane anaesthesia, IV: the role of obesity and the effect of low dose anesthesia on fluoride metabolism and renal function. Can Anesth Soc J 1976; 23: 465–79CrossRefGoogle Scholar
  239. 239.
    Churchill D, Yacoub JM, Siu KP, et al. Toxic nephropathy after low-dose methoxyflurane anesthesia: drug interaction with secobarbital. Can Med Assoc J 1976; 114: 326–8PubMedGoogle Scholar
  240. 240.
    Mazze RI, Cousins MJ. Renal toxicity of anaesthetics: with specific reference to the nephrotoxicity of methoxyflurane. Can Anesth Soc J 1973; 20: 64–80CrossRefGoogle Scholar
  241. 241.
    Mazze RI, Trudell JR, Cousins MJ. Methoxyflurane metabolism and renal disfunction. Anesthesiology 1971; 35: 247–52PubMedCrossRefGoogle Scholar
  242. 242.
    Roman RJ, Carter JR, North WC, et al. Renal tubular site of action of fluoride in Fischer 344 rats. Anesthesiology 1977; 46: 260–4PubMedCrossRefGoogle Scholar
  243. 243.
    Eger El, Smuckler EA, Ferrell LD, et al. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21–30PubMedCrossRefGoogle Scholar
  244. 244.
    Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536–42PubMedCrossRefGoogle Scholar
  245. 245.
    Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anaesthesia in volunteers. Anesthesiology 1977; 46: 265–71PubMedCrossRefGoogle Scholar
  246. 246.
    Kharasch ED, Thummel KE. Identification of cytochrome P450 2E1 as the predominant enzyme catalysing human liver microsomal defluorination of sevoflurane, isoflurane, and methoxyflurane. Anesthesiology 1993; 79: 795–807PubMedCrossRefGoogle Scholar
  247. 247.
    Clive DM, Stoff JS. Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Engl J Med 1984; 310: 563–72PubMedCrossRefGoogle Scholar
  248. 248.
    Ten RM, Torres VE, Milliner DS, et al. Acute interstitial nephritis: immunologie and clinical aspects. Mayo Clin Proc 1988; 63: 921–30PubMedGoogle Scholar
  249. 249.
    Porile JL, Bakris GL, Garella S. Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: a review of its clinical spectrum and effects of steroid therapy. J Clin Pharmacol 1990; 30: 468–75PubMedGoogle Scholar
  250. 250.
    Volland C, Sun H, Dammeyer J, et al. Stereoselective degradation of fenoprofen acyl glucuronide enantiomers and irreversible binding to plasma protein. Drug Metabol Dispos 1991; 19: 1080–6Google Scholar
  251. 251.
    Cassidy MJD, Kerr DNS. Renal disorders. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1991: 303–43Google Scholar
  252. 252.
    Nanra RS. Analgesic-associated nephropathies. In: Massry SG et al., editors. Textbook of nephrology, Vol. 1. Baltimore: William and Wilkins, 1989: 842–8Google Scholar
  253. 253.
    Duggin GG. Mechanisms in the development of analgesic nephropathy. Kidney Int 1980; 18: 553–61PubMedCrossRefGoogle Scholar
  254. 254.
    Shelley JH. Pharmacological mechanisms of analgesic nephropathy. Kidney Int 1978; 13: 15–26PubMedCrossRefGoogle Scholar
  255. 255.
    Stillwell TJ, Benson RC. Cyclophosphamide-induced hemorrhagic cystitis: a review of 100 patients. Cancer 1988; 61: 451–7PubMedCrossRefGoogle Scholar
  256. 256.
    Cox PJ. Cyclophosphamide cystitis — identification of acrolein as the causative agent. Biochem Pharmacol 1979; 28: 2045–9PubMedCrossRefGoogle Scholar
  257. 257.
    Philips FS, Sternberg SS, Cronin AP, et al. Cyclophosphamide and urinary bladder toxicity. Cancer Res 1961; 21: 1577–89PubMedGoogle Scholar
  258. 258.
    Lawrence HJ, Simone J, Aur JA. Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 1975; 36: 1572–6PubMedCrossRefGoogle Scholar
  259. 259.
    Kolb NS, Hunsaker LA, Van der Jagt DL. Aldose reductasecatalysed reduction of acrolein: implications for cyclophosphamide toxicity. Mol Pharmacol 1994; 45: 797–801PubMedGoogle Scholar
  260. 260.
    Droller MJ, Saral R, Santos G. Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology 1982; 20: 256–8PubMedCrossRefGoogle Scholar
  261. 261.
    Primack A. Amelioration of cyclophosphamide-induced cystitis. J Natl Cancer Inst 1971; 47: 223–7PubMedGoogle Scholar
  262. 262.
    Mohiuddin J, Prentice HG, Schey S, et al. Treatment of cyclophosphamide-induced cystitis with prostaglandin E2. Ann Intern Med 1984; 101: 142PubMedGoogle Scholar
  263. 263.
    Brock N, Hilgard P, Pohl J, et al. Pharmacokinetics and mechanism of action of detoxifying low-molecular weight thiols. J Cancer Res Clin Oncol 1984; 17: 1155–63Google Scholar
  264. 264.
    Ormstad K, Uehara N. Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat. FEBS Lett 1982; 150: 354–7PubMedCrossRefGoogle Scholar
  265. 265.
    DeVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urol 1990; 143: 1–7PubMedGoogle Scholar
  266. 266.
    Varini M, Monfardini S. Oral sodium 2-mercaptoethane sulfonate (Mesna, Uromitexan) in ifosfamide therapy: preliminary report. Contrib Oncol 1981; 5: 47–51Google Scholar
  267. 267.
    Johnson WW, Meadows DC. Urinary bladder fibrosis and telengiectasia associated with long-term cyclophosphamide therapy. N Engl J Med 1971; 284: 290–4PubMedCrossRefGoogle Scholar
  268. 268.
    Ansell ID, Castro JE. Carcinoma of the bladder complicating cyclophosphamide therapy. Br J Urol 1975; 47: 413–8PubMedCrossRefGoogle Scholar
  269. 269.
    Fairchild WV, Spence CR, Solomon HD, et al. The incidence of bladder cancer after cyclophosphamide therapy. J Urol 1979; 122: 163–4PubMedGoogle Scholar
  270. 270.
    Melnick S, Cole P, Anderson D, et al. Rates and risks of diethylstilbestrol-related clear-cell adenocarcinoma of the vagina and cervix: an update. N Engl J Med 1987; 316: 514–6PubMedCrossRefGoogle Scholar
  271. 271.
    Balling R, Haaf H, Maydl R, et al. Oxidative and conjugative metabolism of diethylstilbestrol by rabbit preimplantation embryos. Dev Biol 1985; 109: 370–8PubMedCrossRefGoogle Scholar
  272. 272.
    Juchau MR, Lee QP, Fantel AG. Xenobiotic biotransformation/bioactivation in organogenesis-stage conceptal issues: implications for embryotoxicity and teratogenesis. Drug Metab Rev 1992; 24: 195–238PubMedCrossRefGoogle Scholar
  273. 273.
    Krauer B, Dayer P. Fetal drug metabolism and its possible clinical implications. Clin Pharmacokinet 1991; 21: 70–80PubMedCrossRefGoogle Scholar
  274. 274.
    Lindhout D. Pharmacogenetics and drug interactions: role in antiepileptic-drug-induced teratogenesis. Neurology 1992; 42: 43–7PubMedCrossRefGoogle Scholar
  275. 275.
    Hanson J. Teratogen update: fetal hydantoin effects. Teratology 1986; 33: 349–53PubMedCrossRefGoogle Scholar
  276. 276.
    Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 87: 285–90PubMedCrossRefGoogle Scholar
  277. 277.
    Kelly TE. Teratogenicity of anticonvulsant drugs, I: review of the literature. Am J Med Genet 1987; 19: 413–34CrossRefGoogle Scholar
  278. 278.
    Finnell RH, Buehler BA, Kerr BM, et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992; 42: 25–31PubMedCrossRefGoogle Scholar
  279. 279.
    Strickler SM, Miller MA, Andermann E, et al. Genetic predisposition to phenytoin-induced birth defects. Lancet 1985; 2: 746–9PubMedCrossRefGoogle Scholar
  280. 280.
    Buehler BA, Delimont D, van Waes M, et al. Prenatal prediction of risk of the fetal hydantoin syndrome. N Engl J Med 1990; 322: 1567–72PubMedCrossRefGoogle Scholar
  281. 281.
    Kaneko S, Otani K, Fukushima Y, et al. Teratogenicity of anti-epileptic drugs: analysis of possible risk factors. Epilepsia 1988; 29: 459–67PubMedCrossRefGoogle Scholar
  282. 282.
    Kerr BM, Levy RH. Inhibition of epoxide hydrolase by anticonvulsants and the risk of teratogenicity. Lancet 1989; 1: 610–1PubMedCrossRefGoogle Scholar
  283. 283.
    Kerr BM, Rettie AE, Eddy C, et al. Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation. Clin Pharmacol Ther 1989; 46: 82–93PubMedCrossRefGoogle Scholar
  284. 284.
    Ganellin CR. Discovery of cimetidine, ranitidine and other H2-receptor histamine antagonists. In: Ganellin CR, et al., editors. Medicinal Chemistry. London: Academic Press, 1993: 227–55Google Scholar
  285. 285.
    Main BG, Tucker H. Beta blockers. In: Ganellin CR, et al., editors. Medicinal Chemistry. London: Academic Press, 1993: 188–208Google Scholar

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© Adis International Limited 1994

Authors and Affiliations

  • Munir Pirmohamed
    • 1
  • Neil R. Kitteringham
    • 1
  • B. Kevin Park
    • 1
  1. 1.Department of Pharmacology and TherapeuticsUniversity of LiverpoolLiverpoolEngland

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