Skip to main content
SpringerLink
Log in

The Role of Active Metabolites in Drug Toxicity

  • Review Article
  • Drug Safety Concepts
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Committee on Safety of Medicines. CSM update. BMJ 1985; 291: 46

    Article  Google Scholar 

  2. Woolf TF, Jordan RA. Basic concepts in drug metabolism: part I. J Clin Pharmacol 1987; 27: 15–7

    Article  PubMed  CAS  Google Scholar 

  3. Park BK. Metabolic basis of adverse drug reactions. J R Coll Physicians Lond 1986; 20: 195–200

    PubMed  CAS  Google Scholar 

  4. Park BK, Pirmohamed M, Kitteringham NR. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol 1992; 34: 377–95

    Article  PubMed  CAS  Google Scholar 

  5. Williams RT. The metabolism of foreign compounds and the detoxication mechanisms. In: Williams RT, editor. Detoxication mechanisms. New York: John Wiley, 1959: 717–40

    Google Scholar 

  6. Tephly TR, Burchell B. UDP-glucuronyl transferases: a family of detoxifying enzymes. Trends Pharmacol Sci 1990; 11: 276–9

    Article  PubMed  CAS  Google Scholar 

  7. Rawlins MD, Thompson JW. Pathogenesis of adverse drug reactions. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1977: 44

    Google Scholar 

  8. Grahame-Smith DG, Aronson JK, editors. Oxford textbook of clinical pharmacology and drug therapy. Oxford: Oxford University Press, 1992

    Google Scholar 

  9. Watkins PB. Role of cytochrome P450 in drug metabolism and hepatotoxicity. Semin Liver Dis 1990; 10: 235–50

    Article  PubMed  CAS  Google Scholar 

  10. Williams AT, Burk RF. Carbon tetrachloride hepatotoxicity: an example of free radical-mediated injury. Semin Liver Dis 1990; 10: 279–84

    Article  PubMed  CAS  Google Scholar 

  11. Park BK, Coleman JW, Kitteringham NR. Drug disposition and drug hypersensitivity. Biochem Pharmacol 1987; 36: 581–90

    Article  PubMed  CAS  Google Scholar 

  12. Pohl RL, Satoh H, Christ DD, et al. Immunologic and metabolic basis of drug hypersensitivities. Annu Rev Pharmacol 1988; 28: 367–87

    Article  CAS  Google Scholar 

  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: 575–96

    Google Scholar 

  14. Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54: 17–61

    Article  PubMed  CAS  Google Scholar 

  15. Juchau MR. Bioactivation in chemical teratogenesis. Annu Rev Pharmacol Toxicol 1989; 29: 165–87

    Article  PubMed  CAS  Google Scholar 

  16. Pirmohamed M, Kitteringham NR, Park BK. Idiosyncratic reactions to antidepressants: a review of possible mechanisms and predisposing factors. Pharmacol Ther 1992; 53: 105–25

    Article  PubMed  CAS  Google Scholar 

  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, 1985

    Google Scholar 

  18. Zimmerman HJ, editor. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. New York: Appleton-Century Crofts, 1978

    Google Scholar 

  19. Davis M, Williams R. Hepatic disorders. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1991: 245–304

    Google Scholar 

  20. Neuberger JM. Halothane and hepatitis. incidence, predisposing factors and exposure guidelines. Drug Saf 1990; 5: 28–38

    CAS  Google Scholar 

  21. Bray GP. Liver failure induced by paracetamol. BMJ 1993; 306: 157–8

    Article  PubMed  CAS  Google Scholar 

  22. Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10: 267–78

    Article  PubMed  CAS  Google Scholar 

  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: 270–83

    Article  PubMed  CAS  Google Scholar 

  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: 1563–9

    Article  PubMed  CAS  Google Scholar 

  25. Prescott LF. Paracetamol overdosage: pharmacological considerations and clinical management. Drugs 1983; 25: 290–314

    Article  PubMed  CAS  Google Scholar 

  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: 195–202

    CAS  Google Scholar 

  27. Mitchell JR, Jollow DJ, Potter WZ, et al. Acetaminophen-induced hepatic necrosis, I: role of drug metabolism. J Pharmacol Exp Ther 1973; 187: 185–94

    PubMed  CAS  Google Scholar 

  28. Myers LL, Bierschmitt WP, Khairallah EA, et al. Acetaminophen-induced inhibition of hepatic mitochondrial respiration of mice. Toxicol Appl Pharmacol 1988; 93: 378–87

    Article  Google Scholar 

  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: 203–10

    PubMed  CAS  Google Scholar 

  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: 9814–9

    PubMed  CAS  Google Scholar 

  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: 3059–65

    PubMed  CAS  Google Scholar 

  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: 2367–70

    Article  PubMed  CAS  Google Scholar 

  33. Rosen GM, Singletary WVJ, Rauckman EJ, et al. Acetaminophen hepatotoxicity. An alternative mechanism. Biochem Pharmacol 1983; 32: 2053–9

    CAS  Google Scholar 

  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: 157–67

    Article  PubMed  CAS  Google Scholar 

  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: 2125–31

    Article  PubMed  CAS  Google Scholar 

  36. Lauterburg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29: 1153–7

    Article  PubMed  CAS  Google Scholar 

  37. Lieber CS. Biochemical and molecular basis of alcohol induced injury to liver and other tissues. N Engl J Med 1988; 319: 1639–50

    Article  PubMed  CAS  Google Scholar 

  38. Seeff LB, Cuccherini BA, Zimmerman HJ, et al. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986; 104: 399–404

    PubMed  CAS  Google Scholar 

  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: 265–70

    Article  PubMed  CAS  Google Scholar 

  40. De Morais SMF, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert’s syndrome. Gastroenterology 1992; 102: 577–86

    PubMed  Google Scholar 

  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: 125–8

    Article  PubMed  CAS  Google Scholar 

  42. Meredith TJ, Prescott LF, Vale JF. Why do patients still die from paracetamol poisoning? BMJ 1986; 293: 345–6

    Article  PubMed  CAS  Google Scholar 

  43. Harrison PM, Keays R, Bray GP, et al. Improved outcome of paracetamol induced hepatic failure by late administration of acetylcysteine. Lancet 1990; 335: 1572–3

    Article  PubMed  CAS  Google Scholar 

  44. Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303: 1026–9

    Article  PubMed  CAS  Google Scholar 

  45. Albano E, Rundgren M, Harvison PJ, et al. Mechanism of N-acetyl-p-benzoquinoneimine cytotoxicity. Mol Pharmacol 1985; 28: 306–11

    PubMed  CAS  Google Scholar 

  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: 4429–38

    Article  PubMed  CAS  Google Scholar 

  47. Harmon AW. The effectiveness of antioxidants in reducing paracetamol-induced damage subsequent to paracetamol activation. Res Commun Chem Pathol Pharmacol 1985; 49: 215–28

    Google Scholar 

  48. Dreifuss FE, Santilli N, Langer DH, et al. Valproic acid hepatic fatalities: a retrospective review. Neurology. 1987; 37: 379–85

    Article  PubMed  CAS  Google Scholar 

  49. Dreifuss FE, Langer DH, Moline KA, et al. Valproic acid hepatic fatalities — II: US experience since 1984. Neurology. 1989; 39: 201–7

    Article  PubMed  CAS  Google Scholar 

  50. Scheffner D, Konig St, Rauterberg-Ruland I, et al. Fatal liver failure in 16 children with valproate therapy. Epilepsia 1988; 29: 530–42

    Article  PubMed  CAS  Google Scholar 

  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: 525–35

    CAS  Google Scholar 

  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: 81–96

    PubMed  CAS  Google Scholar 

  53. Rettie AE, Rettenmeier AW, Howald WN, et al. Cytochrome P450-catalyzed formation of VPA, a toxic metabolite of valproic acid. Science 1987; 235: 890–3

    Article  PubMed  CAS  Google Scholar 

  54. National Halothane Study. Summary of the National Halothane Study. JAMA 1966; 197: 121–34

    Article  Google Scholar 

  55. Pohl LR. Drug-induced allergic hepatitis. Semin Liver Dis 1990; 10: 305–15

    Article  PubMed  CAS  Google Scholar 

  56. Pohl LR, Kenna JG, Satoh H, et al. Neoantigens associated with halothane hepatitis. Drug Metab Rev 1989; 20: 203–17

    Article  PubMed  CAS  Google Scholar 

  57. Neuberger J, Kenna JG. Halothane hepatitis: a model of immune mediated drug hepatotoxicity. Clin Sci 1987; 72: 263–70

    PubMed  CAS  Google Scholar 

  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: 1635–41

    Article  PubMed  CAS  Google Scholar 

  59. Gut J, Christen U, Huwyler J. Mechanisms of halothane toxicity: novel insights. Pharmacol Ther 1993; 58: 133–55

    Article  PubMed  CAS  Google Scholar 

  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: 833–8

    Article  PubMed  CAS  Google Scholar 

  61. Arria AM, Tarter RE, Van-Thiel DH. Vulnerability to alcoholic liver disease. Recent Dev Alcohol 1991; 9: 185–204

    PubMed  CAS  Google Scholar 

  62. Day CP, Bassendine MF. Genetic predisposition to alcoholic liver disease. Gut 1992; 33: 1444–7

    Article  PubMed  CAS  Google Scholar 

  63. Tuma DJ, Klassen LW. Immune responses to acetaldehyde-protein adducts: role in alcoholic liver disease. Gastroenterology 1992; 103: 1969–73

    PubMed  CAS  Google Scholar 

  64. Zetterman RK. Autoimmunity and alcoholic liver disease. Am J Med 1990; 89: 127–8

    Article  PubMed  CAS  Google Scholar 

  65. Sorrell MF, Leevy CM. Lymphocyte transformation and alcohol liver injury. Gastroenterology 1972; 63: 1020–5

    PubMed  CAS  Google Scholar 

  66. Laskin CA, Vidins E, Blendis LM, et al. Autoantibodies in alcoholic liver disease. Am J Med 1990; 89: 129–33

    Article  PubMed  CAS  Google Scholar 

  67. Niemela O, Klajner F, Orrego H, et al. Antibodies against acetaldehyde-modified protein epitopes in human alcoholics. Hepatology 1987; 7: 1210–4

    Article  PubMed  CAS  Google Scholar 

  68. Niemela O, Juvonen T, Parkkila S. Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest 1991; 87: 1367–74

    Article  PubMed  CAS  Google Scholar 

  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: 509–17

    PubMed  CAS  Google Scholar 

  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: 1480–501

    Google Scholar 

  71. Kao J, Carver MP. Cutaneous metabolism of xenobiotics. Drug Metab Rev 1990; 22: 363–410

    Article  PubMed  CAS  Google Scholar 

  72. Mukhtar H, Khan WA. Cutaneous cytochrome P-450. rug Metab Rev 1989; 20: 657–73

    Article  CAS  Google Scholar 

  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: 465–75

    Article  PubMed  CAS  Google Scholar 

  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: 1847–51

    Article  PubMed  Google Scholar 

  75. Kao J. Estimating the contribution by skin to systemic metabolism. Ann NY Acad Sci 1988; 548: 90–6

    Article  PubMed  CAS  Google Scholar 

  76. Longley BJ, Braverman IM, Edelson RL. Immunology and the skin. Current concepts. Ann NY Acad Sci 1988; 548: 225–32

    Article  PubMed  CAS  Google Scholar 

  77. Raviglione MC, Pablos-Mendez A, Battan R. Clinical features and management of severe dermatological reactions to drugs. Drug Saf 1990; 5: 39–64

    Article  PubMed  CAS  Google Scholar 

  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: 43–7

    Article  PubMed  CAS  Google Scholar 

  79. Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400

    Article  PubMed  CAS  Google Scholar 

  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: 741–9

    Article  PubMed  CAS  Google Scholar 

  81. Shear NH, Spielberg SP, Cannon M, et al. Anticonvulsant hypersensitivity syndrome: in vitro risk assessment. J Clin Invest 1988; 82: 1826–32

    Article  PubMed  CAS  Google Scholar 

  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: 1675–82

    Article  PubMed  CAS  Google Scholar 

  83. Spielberg SP, Gordon GB, Blake DA, et al. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med 1981; 305: 722–7

    Article  PubMed  CAS  Google Scholar 

  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: 2307–14

    Article  PubMed  CAS  Google Scholar 

  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: 577–88

    Article  PubMed  CAS  Google Scholar 

  86. Riley RJ, Kitteringham NR, Park BK. Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro. Br J Clin Pharmacol 1989; 28: 482–7

    Article  PubMed  CAS  Google Scholar 

  87. Spielberg SP. In vitro assessment of pharmacogenetic susceptibility to toxic drug metabolites in humans. Fed Proc 1984; 43: 2308–13

    PubMed  CAS  Google Scholar 

  88. Spielberg SP. Acetaminophen toxicity in human lymphocytes in vitro. J Pharmacol Exp Ther 1980; 213: 395–8

    PubMed  CAS  Google Scholar 

  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: 286–9

    Google Scholar 

  90. Shear NH, Spielberg SP. In vitro evaluation of a toxic metabolite of sulfadiazine. Can J Physiol Pharmacol 1985; 63: 1370–2

    Article  PubMed  CAS  Google Scholar 

  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: 900–6

    PubMed  CAS  Google Scholar 

  92. van der Ven AJ, Koopmans PP, Vree TB, et al. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991; 2: 1991

    Google Scholar 

  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: 239–65

    Google Scholar 

  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: 1107–9

    Article  PubMed  CAS  Google Scholar 

  95. Russell GI, Bing RF, Jones JAG, et al. Hydralazine sensitivity: clinical features, autoantibody changes and HLA-DR phenotype. QJ Med 1987; 65: 845–52

    CAS  Google Scholar 

  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: 1157–9

    Article  PubMed  CAS  Google Scholar 

  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: 1382–5

    Article  PubMed  CAS  Google Scholar 

  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: 463–8

    Article  PubMed  CAS  Google Scholar 

  99. Claas FHJ. Drug-induced immune granulocytopenia. Baillieres Clin Immunol Allergy 1987; 1: 357–67

    Google Scholar 

  100. Pisciotta AV. Drug-induced agranulocytosis: peripheral destruction of polymorphonuclear leukocytes and their marrow precursors. Blood Rev 1990; 4: 226–37

    Article  PubMed  CAS  Google Scholar 

  101. Vincent PC. Drug-induced aplastic anaemia and agranulocytosis: incidence and mechanisms. Drugs 1986; 31: 52–63

    Article  PubMed  CAS  Google Scholar 

  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: 744–51

    PubMed  CAS  Google Scholar 

  103. Hurst JK, Barrette WC. Leukocytic oxygen activation and microbicidal oxidative toxins. Crit Rev Biochem Mol Biol 1989; 24: 271–328

    Article  PubMed  CAS  Google Scholar 

  104. Fraiser LH, Kanekal S, Kehrer JP. Cyclophophamide toxicity. Characterising and avoiding the problem. Drugs 1991; 42: 781–95

    Article  PubMed  CAS  Google Scholar 

  105. Kaufman DW, et al., editors. The drug etiology of agranulocytosis and anemia, New York: Oxford University Press, 1991

    Google Scholar 

  106. Gerson WT, Fine DG, Spielberg SP, et al. Anticonvulsant-induced aplastic anaemia: increased susceptibility to toxic drug metabolites in vitro. Blood 1983; 61: 889–93

    PubMed  CAS  Google Scholar 

  107. Chaplin S. Bone marrow depression due to mianserin, phenylbutazone, oxyphenbutazone and chloramphenicol — part I. Adverse Drug React Acute Pois Rev 1986; 2: 97–136

    Google Scholar 

  108. Ichihara S, Tomisawa H, Fukazawa H, et al. Invovlement of leukocytes in the oxygenation and chlorination reaction of phenylbutazone. Biochem Pharmacol 1986; 35: 3935–9

    Article  PubMed  CAS  Google Scholar 

  109. Yunis AA. Chloramphenicol toxicity? 25 years of research. Am J Med 1989; 87: 44–8

    Google Scholar 

  110. Yunis AA, Miller AM, Salem Z, et al. Nitrosochloramphenicol: possible mediator in chloramphenicol-nduced aplastic anemia. J Lab Clin Med 1980; 96: 36–46

    PubMed  CAS  Google Scholar 

  111. Yunis AA. Chloramphenicol: relation of structure to activity and toxicity. Annu Rev Pharmacol Toxicol 1988; 28: 83–100

    Article  PubMed  CAS  Google Scholar 

  112. Ascheri M, Eyer P, Kampffmeyer H. Formation and disposition of nitrosochloramphenicol in rat liver. Biochem Pharmacol 1985; 34: 3755–63

    Article  Google Scholar 

  113. Jimenez JJ, Isildar M, Yunis AA. Bone marrow damage induced by chlormphenicol may be mediated by its bacterial metabolites. Blood 1987; 70: 1180–5

    PubMed  CAS  Google Scholar 

  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: 40–6

    Article  PubMed  CAS  Google Scholar 

  115. Isildar M, Abou-Khalil WH, Jimenez JJ, et al. Aerobic nitroreduction of dehydrochloramphenicol by human bone marrow. Toxicol Appl Pharmacol 1988; 94: 305–10

    Article  PubMed  CAS  Google Scholar 

  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: 33–7

    Article  PubMed  CAS  Google Scholar 

  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: 178–80

    Article  PubMed  CAS  Google Scholar 

  118. Harris BE, Diasio RB. Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora. Antimicrob Agents Chemother 1986; 29: 44–8

    Article  PubMed  CAS  Google Scholar 

  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: 718–24

    CAS  Google Scholar 

  120. Perkocha LA, Rodgers GM. Hematologic aspects of human immunodeficiency virus infection: laboratory and clinical considerations. Am J Hematol 1988; 29: 94–105

    Article  PubMed  CAS  Google Scholar 

  121. Zon LI, Arkin C, Groopman JE. Hematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol 1987; 66: 251–6

    Article  PubMed  CAS  Google Scholar 

  122. McLeod GX, Hammer SM. Zidovudine: five years later. Ann Intern Med 1992; 117: 487–501

    PubMed  CAS  Google Scholar 

  123. Boyar A, Beall G. HIV-seropositive thrombocytopenia: the action of zidovudine. AIDS 1991; 5: 1351–6

    Article  PubMed  CAS  Google Scholar 

  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: 1779–84

    Article  PubMed  CAS  Google Scholar 

  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: 9–14

    PubMed  CAS  Google Scholar 

  126. Lutton JD, Mathew A, Levere RD, et al. Role of heme metabolism in AZT-induced bone marrow toxicity. Am J Hematol 1990; 35: 1–5

    Article  PubMed  CAS  Google Scholar 

  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: 189

    Google Scholar 

  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: 258–66

    PubMed  CAS  Google Scholar 

  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: 319–24

    Article  PubMed  Google Scholar 

  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: 121–32

    Article  PubMed  CAS  Google Scholar 

  131. Uetrecht JP. The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions. Drug Metab Rev 1992; 24: 299–366

    Article  PubMed  CAS  Google Scholar 

  132. Lieberman JA, Alvir JM. A report of clozapine-induced agranulocytosis in the United States. Incidence and risk factors. Drug Saf 1992; 7Suppl. 1: 1–2

    Article  PubMed  Google Scholar 

  133. Safferman A, Lieberman JA, Kane JM, et al. Update on the clinical efficacy and side effects of clozapine. Schizophr Bull 1991; 17: 247–61

    PubMed  CAS  Google Scholar 

  134. Fischer V, Haar JA, Greiner L, et al. Possible role of free radical formation in clozapine (Clozaril)-induced agranulocytosis. Mol Pharmacol 1991; 40: 846–53

    PubMed  CAS  Google Scholar 

  135. Jann MW. Clozapine. Pharmacotherapy 1991; 11: 179–95

    PubMed  CAS  Google Scholar 

  136. Baldessarini RJ, Frankenburg FR. Clozapine. A novel antipsychotic agent. N Engl J Med 1991; 324: 746–54

    Article  PubMed  CAS  Google Scholar 

  137. Ammus S, Yunis AA. Drug-induced red cell dyscrasias. Blood Rev 1989; 3: 71–82

    Article  PubMed  CAS  Google Scholar 

  138. Robicsek F. Acute methemoglobinemia during cardiopulmonary bypass caused by intravenous nitroglycerin infusion. J Thorac Cardiovasc Surg 1985; 90: 931–4

    PubMed  CAS  Google Scholar 

  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: 389–95

    Article  PubMed  CAS  Google Scholar 

  140. Grossman SJ, Jollow DJ. Role of dapsone hydroxylamine in dapsone induced hemolytic anemia. J Pharmacol Exp Ther 1988; 244: 118–25

    PubMed  CAS  Google Scholar 

  141. Fleming CM, Branch RA, Wilkinson GR, et al. Human liver microsomal N-hydroxylation of dapsone by cytochrome P-4503A4. Mol Pharmacol 1992; 41: 975–80

    PubMed  CAS  Google Scholar 

  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: 829–38

    Article  PubMed  CAS  Google Scholar 

  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: 626P

    Google Scholar 

  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: 761–7

    Article  PubMed  CAS  Google Scholar 

  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: 244–9

    Article  PubMed  CAS  Google Scholar 

  146. Pounder RE, Craven ER, Henthorn JS, et al. Red cell abnormalities associated with sulphasalazine maintenance therapy for ulcerative colitis. Gut 1975; 16: 181–5

    Article  PubMed  CAS  Google Scholar 

  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: 303–10

    Article  PubMed  CAS  Google Scholar 

  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: 222–6

    Article  PubMed  CAS  Google Scholar 

  149. Eichelbaum M, Gross AS. The genetic polymorphism of debrisoquine/sparteine metabolism — clinical aspects. Pharmacol Ther 1990; 46: 377–94

    Article  PubMed  CAS  Google Scholar 

  150. Timbrell JA. Principles of biochemical toxicology. London: Taylor and Francis, 1991

    Google Scholar 

  151. Brodie BB, Axelrod J. The fate of acetophenetidin and its metabolites in biological material. J Pharmacol Exp Ther 1949; 9: 58–67

    Google Scholar 

  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: 137–57

    Google Scholar 

  153. Anonymous. Trouble with nomifensine. Drug Ther Bull 1985; 23: 98–100

    Google Scholar 

  154. Bournerias F, Habibi B. Nomifensine-induced immune haemolytic anaemia and impaired renal function. Lancet 1979; 2: 95–6

    Article  PubMed  CAS  Google Scholar 

  155. Prescott LF, Illingworth RN, Critchley JAJH, et al. Acute haemolysis and renal failure after nomifensine overdosage. BMJ 1980; 281: 1392–3

    Article  PubMed  CAS  Google Scholar 

  156. Salama A, Mueller-Eckhardt C. The role of metabolite-specific antibodies in nomifensine-dependent immune haemolytic anaemia. N Engl J Med 1985; 313: 469–74

    Article  PubMed  CAS  Google Scholar 

  157. Weiss ME, Adkinson MF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy 1988; 18: 515–40

    Article  PubMed  CAS  Google Scholar 

  158. Page MI. The mechanisms of reaction of β-lactam antibiotics. Acc Chem Res 1984; 17: 144–51

    Article  CAS  Google Scholar 

  159. Levine BB. Immunochemical mechanisms involved in penicillin hypersensitivity in experimental animals and in human beings. Fed Proc 1965; 24: 45–50

    PubMed  CAS  Google Scholar 

  160. Parker CW. Immunochemical mechanisms in penicillin allergy. Fed Proc 1965; 24: 51–4

    PubMed  CAS  Google Scholar 

  161. Parker CW. Allergic reactions in man. Pharmacol Rev 1982; 34: 85–104

    PubMed  CAS  Google Scholar 

  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: 5–47

    Article  PubMed  CAS  Google Scholar 

  163. Smith PC, McDonagh AF, Benet LZ. Irreversible binding of zomepirac to plasma protein in vitro and in vivo. J Clin Invest 1986; 77: 934–9

    Article  PubMed  CAS  Google Scholar 

  164. Murray MD, Brater DC. Renal toxicity of the nonsteroidal antiinflammatory drugs. Annu Rev Pharmacol Toxicol 1993; 32: 435–65

    Article  Google Scholar 

  165. Day RO, Graham GG, Williams KM, et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs. Pharmacol Ther 1987; 33: 383–433

    Article  PubMed  CAS  Google Scholar 

  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: 147–50

    Article  PubMed  CAS  Google Scholar 

  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: 231–8

    Article  PubMed  CAS  Google Scholar 

  168. MacConnell TJ, Stanners AJ. Torsades de pointes complicating treatment with terfenadine. BMJ 1991; 302: 1469

    Article  PubMed  CAS  Google Scholar 

  169. Matthews DR, McNutt B, Okerholm R, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1991; 266: 2375–6

    Article  Google Scholar 

  170. Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades de pointes occurring in association with terfenadine use. JAMA 1990; 264: 2788–90

    Article  PubMed  CAS  Google Scholar 

  171. Garteiz DA, Hook RH, Walker BJ, et al. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittelforschung 1982; 32: 1185–90

    PubMed  CAS  Google Scholar 

  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: 161

    Article  Google Scholar 

  173. Honig P, Wortham D, Zamani K, et al. The pharmacokinetics and cardiac consequences of the terfenadine-ketoconazole interaction. Clin Pharmacol Ther 1993; 53: 206

    Article  Google Scholar 

  174. Larrey D, Funck-Brentano C, Breil P. Effects of erythromycin on hepatic drug metabolising enzymes in humans. Biochem Pharmacol 1983; 32: 1063–8

    Article  PubMed  CAS  Google Scholar 

  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: 1487–93

    Article  PubMed  CAS  Google Scholar 

  176. Sheets JJ, Mason JI. Ketoconazole: a potent inhibitor of cytochrome P-450 dependent drug metabolism in rat liver. Drug Metab Dispos 1984; 12: 603–8

    PubMed  CAS  Google Scholar 

  177. Eller M, Stoltz M, Okerholm R, et al. Effect of hepatic disease on terfenadine and terfenadine metabolite pharmacokinetics. Clin Pharmacol Ther 1993; 53: 162

    Google Scholar 

  178. Russell T, Eller M, Hutcheson S, et al. Effect of renal disease on terfenadine metabolite pharmacokinetics. Clin Pharmacol Ther 1993; 53: 162

    Google Scholar 

  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: 140A

    Google Scholar 

  180. Porembka DT, Lowder JN, Orlowski JP, et al. Etiology and management of doxorubicin cardiotoxicity. Crit Care Med 1989; 17: 569–72

    Article  PubMed  CAS  Google Scholar 

  181. Lenaz LN, Page JA. Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat Rev 1976; 3: 111–20

    Article  PubMed  CAS  Google Scholar 

  182. Anonymous. Childhood cancer, anthracyclines and the heart. Lancet 1992; 339: 1388–9

    Article  Google Scholar 

  183. Pratt CB, Ransom JL, Evans WE. Age-related adriamycin cardiotoxicity in children. Cancer Treat Rep 1978; 62: 1381–5

    PubMed  CAS  Google Scholar 

  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: 200–8

    Article  Google Scholar 

  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: 285–95

    PubMed  CAS  Google Scholar 

  186. Myers CE, McGuire WP, Liss RH, et al. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977; 197: 165–7

    Article  PubMed  CAS  Google Scholar 

  187. Olson RD, Mushlin PS. Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 1990; 4: 3076–86

    PubMed  CAS  Google Scholar 

  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: 450–4

    PubMed  CAS  Google Scholar 

  189. Sinha BK, Politi PM. Anthracyclines. Canc Chemother Biol Response Modif 1990; 11: 45–57

    CAS  Google Scholar 

  190. Odom AL, Hatwig CA, Stanley JS, et al. Biochemical determinants of adriamycin toxicity in mouse liver, heart and intestine. Biochem Pharmacol 1992; 43: 831–6

    Article  PubMed  CAS  Google Scholar 

  191. Legha SS, Benjamin RS, Makay B. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982; 96: 133–9

    PubMed  CAS  Google Scholar 

  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: 61–9

    Article  PubMed  Google Scholar 

  193. Devereux TR, Domin BA, Philpot RM. Xenobiotic metabolism by isolated pulmonary cells. Pharmacol Ther 1989; 41: 243–56

    Article  PubMed  CAS  Google Scholar 

  194. Adesnik M, Atchison M. Genes for cytochrome P-450 and their regulation. CRC Crit Rev Biochem 1986; 19: 247–305

    Article  PubMed  CAS  Google Scholar 

  195. Boyd MR. Biochemical mechanisms in chemical-induced lung injury: roles of metabolic activation. CRC Crit Rev Toxicol 1980; 7: 103–76

    Article  CAS  Google Scholar 

  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: 713–5

    Article  PubMed  CAS  Google Scholar 

  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: 5–12

    Google Scholar 

  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: 364–72

    PubMed  CAS  Google Scholar 

  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: 353–63

    PubMed  CAS  Google Scholar 

  200. Jerina DM, Daly JW. Arene oxides: a new aspect of drug metabolism. Science 1974; 185: 573–82

    Article  PubMed  CAS  Google Scholar 

  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: 391–401

    CAS  Google Scholar 

  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: 491–8

    PubMed  CAS  Google Scholar 

  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: 1529–38

    Article  PubMed  CAS  Google Scholar 

  204. Smith LL. Mechanism of paraquat toxicity in lung and its relevance to treatment. Hum Toxicol 1987; 6: 31–6

    Article  PubMed  CAS  Google Scholar 

  205. Gage JC. Action of paraquat and diquat on the respiration of liver cell fractions. Biochem J 1968; 109: 757–61

    PubMed  CAS  Google Scholar 

  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: 1763–7

    Article  PubMed  CAS  Google Scholar 

  207. Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clin Chest Med 1990; 11: 1–20

    PubMed  CAS  Google Scholar 

  208. Patel JM. Metabolism and pulmonary toxicity of cyclophosphamide. Pharmacol Ther 1990; 47: 137–46

    Article  PubMed  CAS  Google Scholar 

  209. Smith RD, Kehrer JP. Cooxidation of cyclophosphamide as an alternative pathway for its bioactivation and lung toxicity. Cancer Res 1991; 51: 542–8

    PubMed  CAS  Google Scholar 

  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: 1091–6

    Article  PubMed  CAS  Google Scholar 

  211. Boyd MR, Stiko AW, Sasame HA. Metabolic activation of nitrofurantoin — possible implications for carcinogenesis. Biochem Pharmacol 1979; 28: 601–6

    Article  PubMed  CAS  Google Scholar 

  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: 89–95

    CAS  Google Scholar 

  213. Spielberg SP, Gordon GB. Nitrofurantoin cytotoxicity. In vitro assessment of risk based on glutathione metabolism. J Clin Invest 1981; 67: 37–41

    Article  PubMed  CAS  Google Scholar 

  214. Calne DB, Langsten JW. Aetiology of Parkinson’s disease. Lancet 1983; 2: 1457–9

    Article  PubMed  CAS  Google Scholar 

  215. Langston JW. MPTP and Parkinson’s disease. Trends Neurosci 1985; 8: 79–83

    Article  CAS  Google Scholar 

  216. Lewin R. Trail of ironies to Parkinson’s disease. Science 1984; 224: 1083–5

    Article  PubMed  CAS  Google Scholar 

  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: 291–332

    Article  PubMed  CAS  Google Scholar 

  218. Marsden CD. Parkinson’s disease. Postgrad Med J 1992; 68: 538–43

    Article  PubMed  CAS  Google Scholar 

  219. Chiba K, Trevor A, Castagnoli N. Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem Biophys Res Commun 1984; 120: 574–8

    Article  PubMed  CAS  Google Scholar 

  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: 2173–7

    Article  PubMed  CAS  Google Scholar 

  221. D’Amato RJ, Alexander GM, Schwartzman RJ, et al. Evidence for neuromelanin involvement in MPTP-induced neurotoxicity. Nature 1987; 327: 324–6

    Article  PubMed  Google Scholar 

  222. D’Amato RJ, Alexander GM, Schwartzman RJ, et al. Neuromelanin: a role in MPTP-induced neurotoxicity. Life Sci 1987; 40: 705–12

    Article  PubMed  Google Scholar 

  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: 653–8

    Article  PubMed  Google Scholar 

  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: 1501–7

    Article  PubMed  CAS  Google Scholar 

  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: 4573–4

    Article  PubMed  CAS  Google Scholar 

  226. The Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–71

    Article  Google Scholar 

  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: 176–83

    Article  Google Scholar 

  228. Kofman OS. Deprenyl: protective vs. symptomatic effect. Can J Neurol Sci 1991; 18: 83–5

    PubMed  CAS  Google Scholar 

  229. Kofman OS. Protective effect or symptomatic effect of deprenyl? N Engl J Med 1993; 328: 1715

    PubMed  CAS  Google Scholar 

  230. Henderson CJ, Wolf CR. Evidence that the androgen receptor mediates sexual differentiation of mouse renal cytochrome P450 expression. Biochem J 1991; 278: 499–503

    PubMed  CAS  Google Scholar 

  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: 675–81

    PubMed  CAS  Google Scholar 

  232. Wolf CR. Individuality in cytochrome P450 expression and its association with the nephrotoxic and carcinogenic effects of chemicals. IARC Sci Publ 1991; 281–7

    Google Scholar 

  233. Yaqoob M, Bell GM, Stevenson A, et al. Renal impairment with chronic hydrocarbon exposure. Q J Med 1993; 86: 165–74

    PubMed  CAS  Google Scholar 

  234. Benitz KF, Diermeier HF. Renal toxicity of tetracycline degradation products. Proc Soc Exp Biol Med 1964; 115: 930–5

    PubMed  CAS  Google Scholar 

  235. Lowe MB, Obst D, Tapp E. Renal damage caused by anhydro 4-EPI-tetracycline. Arch Pathol 1966; 81: 362–4

    PubMed  CAS  Google Scholar 

  236. Toomath RJ, Morrison RB. Renal failure following methoxyflurane analgesia. NZ Med J 1987; 100: 707–8

    CAS  Google Scholar 

  237. Mazze RI, Shue GL, Jackson SH. Renal dysfunction associated with methoxyflurane anesthesia: a randomized, prospective clinical evaluation. JAMA 1971; 216: 278–80

    Article  PubMed  CAS  Google Scholar 

  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: 465–79

    Article  CAS  Google Scholar 

  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: 326–8

    PubMed  CAS  Google Scholar 

  240. Mazze RI, Cousins MJ. Renal toxicity of anaesthetics: with specific reference to the nephrotoxicity of methoxyflurane. Can Anesth Soc J 1973; 20: 64–80

    Article  CAS  Google Scholar 

  241. Mazze RI, Trudell JR, Cousins MJ. Methoxyflurane metabolism and renal disfunction. Anesthesiology 1971; 35: 247–52

    Article  PubMed  CAS  Google Scholar 

  242. Roman RJ, Carter JR, North WC, et al. Renal tubular site of action of fluoride in Fischer 344 rats. Anesthesiology 1977; 46: 260–4

    Article  PubMed  CAS  Google Scholar 

  243. Eger El, Smuckler EA, Ferrell LD, et al. Is enflurane hepatotoxic? Anesth Analg 1986; 65: 21–30

    Article  PubMed  Google Scholar 

  244. Mazze RI, Cousins MJ, Barr GA. Renal effects and metabolism of isoflurane in man. Anesthesiology 1974; 40: 536–42

    Article  PubMed  CAS  Google Scholar 

  245. Mazze RI, Calverley RK, Smith NT. Inorganic fluoride nephrotoxicity: prolonged enflurane and halothane anaesthesia in volunteers. Anesthesiology 1977; 46: 265–71

    Article  PubMed  CAS  Google Scholar 

  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: 795–807

    Article  PubMed  CAS  Google Scholar 

  247. Clive DM, Stoff JS. Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Engl J Med 1984; 310: 563–72

    Article  PubMed  CAS  Google Scholar 

  248. Ten RM, Torres VE, Milliner DS, et al. Acute interstitial nephritis: immunologie and clinical aspects. Mayo Clin Proc 1988; 63: 921–30

    PubMed  CAS  Google Scholar 

  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: 468–75

    PubMed  CAS  Google Scholar 

  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: 1080–6

    CAS  Google Scholar 

  251. Cassidy MJD, Kerr DNS. Renal disorders. In: Davies DM, editor. Textbook of adverse drug reactions. Oxford: Oxford University Press, 1991: 303–43

    Google Scholar 

  252. Nanra RS. Analgesic-associated nephropathies. In: Massry SG et al., editors. Textbook of nephrology, Vol. 1. Baltimore: William and Wilkins, 1989: 842–8

    Google Scholar 

  253. Duggin GG. Mechanisms in the development of analgesic nephropathy. Kidney Int 1980; 18: 553–61

    Article  PubMed  CAS  Google Scholar 

  254. Shelley JH. Pharmacological mechanisms of analgesic nephropathy. Kidney Int 1978; 13: 15–26

    Article  PubMed  CAS  Google Scholar 

  255. Stillwell TJ, Benson RC. Cyclophosphamide-induced hemorrhagic cystitis: a review of 100 patients. Cancer 1988; 61: 451–7

    Article  PubMed  CAS  Google Scholar 

  256. Cox PJ. Cyclophosphamide cystitis — identification of acrolein as the causative agent. Biochem Pharmacol 1979; 28: 2045–9

    Article  PubMed  CAS  Google Scholar 

  257. Philips FS, Sternberg SS, Cronin AP, et al. Cyclophosphamide and urinary bladder toxicity. Cancer Res 1961; 21: 1577–89

    PubMed  CAS  Google Scholar 

  258. Lawrence HJ, Simone J, Aur JA. Cyclophosphamide-induced hemorrhagic cystitis in children with leukemia. Cancer 1975; 36: 1572–6

    Article  PubMed  CAS  Google Scholar 

  259. Kolb NS, Hunsaker LA, Van der Jagt DL. Aldose reductasecatalysed reduction of acrolein: implications for cyclophosphamide toxicity. Mol Pharmacol 1994; 45: 797–801

    PubMed  CAS  Google Scholar 

  260. Droller MJ, Saral R, Santos G. Prevention of cyclophosphamide-induced hemorrhagic cystitis. Urology 1982; 20: 256–8

    Article  PubMed  CAS  Google Scholar 

  261. Primack A. Amelioration of cyclophosphamide-induced cystitis. J Natl Cancer Inst 1971; 47: 223–7

    PubMed  CAS  Google Scholar 

  262. Mohiuddin J, Prentice HG, Schey S, et al. Treatment of cyclophosphamide-induced cystitis with prostaglandin E2. Ann Intern Med 1984; 101: 142

    PubMed  CAS  Google Scholar 

  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: 1155–63

    Google Scholar 

  264. Ormstad K, Uehara N. Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat. FEBS Lett 1982; 150: 354–7

    Article  PubMed  CAS  Google Scholar 

  265. DeVries CR, Freiha FS. Hemorrhagic cystitis: a review. J Urol 1990; 143: 1–7

    PubMed  CAS  Google Scholar 

  266. Varini M, Monfardini S. Oral sodium 2-mercaptoethane sulfonate (Mesna, Uromitexan) in ifosfamide therapy: preliminary report. Contrib Oncol 1981; 5: 47–51

    Google Scholar 

  267. Johnson WW, Meadows DC. Urinary bladder fibrosis and telengiectasia associated with long-term cyclophosphamide therapy. N Engl J Med 1971; 284: 290–4

    Article  PubMed  CAS  Google Scholar 

  268. Ansell ID, Castro JE. Carcinoma of the bladder complicating cyclophosphamide therapy. Br J Urol 1975; 47: 413–8

    Article  PubMed  CAS  Google Scholar 

  269. Fairchild WV, Spence CR, Solomon HD, et al. The incidence of bladder cancer after cyclophosphamide therapy. J Urol 1979; 122: 163–4

    PubMed  CAS  Google Scholar 

  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: 514–6

    Article  PubMed  CAS  Google Scholar 

  271. Balling R, Haaf H, Maydl R, et al. Oxidative and conjugative metabolism of diethylstilbestrol by rabbit preimplantation embryos. Dev Biol 1985; 109: 370–8

    Article  PubMed  CAS  Google Scholar 

  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: 195–238

    Article  PubMed  CAS  Google Scholar 

  273. Krauer B, Dayer P. Fetal drug metabolism and its possible clinical implications. Clin Pharmacokinet 1991; 21: 70–80

    Article  PubMed  CAS  Google Scholar 

  274. Lindhout D. Pharmacogenetics and drug interactions: role in antiepileptic-drug-induced teratogenesis. Neurology 1992; 42: 43–7

    Article  PubMed  CAS  Google Scholar 

  275. Hanson J. Teratogen update: fetal hydantoin effects. Teratology 1986; 33: 349–53

    Article  PubMed  CAS  Google Scholar 

  276. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 87: 285–90

    Article  PubMed  CAS  Google Scholar 

  277. Kelly TE. Teratogenicity of anticonvulsant drugs, I: review of the literature. Am J Med Genet 1987; 19: 413–34

    Article  Google Scholar 

  278. Finnell RH, Buehler BA, Kerr BM, et al. Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis. Neurology 1992; 42: 25–31

    Article  PubMed  CAS  Google Scholar 

  279. Strickler SM, Miller MA, Andermann E, et al. Genetic predisposition to phenytoin-induced birth defects. Lancet 1985; 2: 746–9

    Article  PubMed  CAS  Google Scholar 

  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: 1567–72

    Article  PubMed  CAS  Google Scholar 

  281. Kaneko S, Otani K, Fukushima Y, et al. Teratogenicity of anti-epileptic drugs: analysis of possible risk factors. Epilepsia 1988; 29: 459–67

    Article  PubMed  CAS  Google Scholar 

  282. Kerr BM, Levy RH. Inhibition of epoxide hydrolase by anticonvulsants and the risk of teratogenicity. Lancet 1989; 1: 610–1

    Article  PubMed  CAS  Google Scholar 

  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: 82–93

    Article  PubMed  CAS  Google Scholar 

  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: 227–55

    Google Scholar 

  285. Main BG, Tucker H. Beta blockers. In: Ganellin CR, et al., editors. Medicinal Chemistry. London: Academic Press, 1993: 188–208

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, University of Liverpool, PO Box 147, Liverpool, L69 3BX, England

    Munir Pirmohamed, Neil R. Kitteringham & B. Kevin Park

Authors
  1. Munir Pirmohamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neil R. Kitteringham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Kevin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pirmohamed, M., Kitteringham, N.R. & Kevin Park, B. The Role of Active Metabolites in Drug Toxicity. Drug-Safety 11, 114–144 (1994). https://doi.org/10.2165/00002018-199411020-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199411020-00006

Keywords

Search

Navigation