Skip to main content

Advertisement

Log in

Role of bioactivation in drug-induced hypersensitivity reactions

  • Published:
The AAPS Journal Aims and scope Submit manuscript

Abstract

Drug-induced hypersensitivity reactions are a major problem in both clinical treatment and drug development. This review covers recent developments in our understanding of the pathogenic mechanisms involved, with special focus on the potential role of metabolism and bioactivation in generating a chemical signal for activation of the immune system. The possible role of haptenation and neoantigen formation is discussed, alongside recent findings that challenge this paradigm. Additionally, the essential role of costimulation is examined, as are the potential points whereby costimulation may be driven by reactive metabolites. The relevance of local generation of metabolites in determining the location and character of a reaction is also covered.

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

Access this article

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. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.JAMA. 1998;279:1200–1205.

    Article  CAS  PubMed  Google Scholar 

  2. Kvasz M, Allen IE, Gordon MJ, et al. Adverse drug reactions in hospitalized patients: a critique of a meta-analysis.MedGenMed. 2000;2:E3.

    CAS  PubMed  Google Scholar 

  3. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients.BMJ. 2004;329:15–19.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rawlins M, Thompson J. Mechanisms of adverse drug reactions. In: Davies D, ed.Textbook of Adverse Drug Reactions. 4th ed. Oxford, England: Oxford University Press; 1991:18–45.

    Google Scholar 

  5. Sullivan JR, Shear NH. The drug hypersensitivity syndrome: what is the pathogenesis?Arch Dermatol. 2001;137:357–364.

    CAS  PubMed  Google Scholar 

  6. Park BK, Pirmohamed M, Kitteringham NR. Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective.Chem Res Toxicol. 1998;11:969–988.

    Article  CAS  PubMed  Google Scholar 

  7. Naisbitt DJ. Drug hypersensitivity reactions in skin: understanding mechanisms and the development of diagnostic and predictive tests.Toxicology. 2004;194:179–196.

    Article  CAS  PubMed  Google Scholar 

  8. Pichler WJ, Yawalkar N, Britschgi M, et al. Cellular and molecular pathophysiology of cutaneous drug reactions.Am J Clin Dermatol. 2002;3:229–238.

    Article  PubMed  Google Scholar 

  9. Naisbitt DJ, Britschgi M, Wong G, et al. Hypersensitivity reactions to carbamazepine: characterization of the specificity, phenotype, and cytokine profile of drug-specific T cell clones.Mol Pharmacol. 2003;63:732–741.

    Article  CAS  PubMed  Google Scholar 

  10. Naisbitt DJ, Farrell J, Chamberlain PJ, et al. Characterization of the T-cell response in a patient with phenindione hypersensitivity.J Pharmacol Exp Ther. 2005;313:1058–1065.

    Article  CAS  PubMed  Google Scholar 

  11. Naisbitt DJ, Farrell J, Wong G, et al. Characterization of drug-specific T cells in lamotrigine hypersensitivity.J Allergy Clin Immunol. 2003;111:1393–1403.

    Article  CAS  PubMed  Google Scholar 

  12. Pichler WJ, Zanni M, von Greyerz S, Schnyder B, Mauri-Hellweg D, Wendland T. High IL-5 production by human drug-specific T cell clones.Int Arch Allergy Immunol. 1997;113:177–180.

    Article  CAS  PubMed  Google Scholar 

  13. Schnyder B, Mauri-Hellweg D, Zanni M, Bettens F, Pichler WJ. Direct, MHC-dependent presentation of the drug sulfamethoxazole to human alphabeta T cell clones.J Clin Invest. 1997;100:136–141.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sieben S, Kawakubo Y, Al Masaoudi T, Merk HF, Blomeke B. Delayed-type hypersensitivity reaction to paraphenylenediamine is mediated by 2 different pathways of antigen recognition by specific alphabeta human T-cell clones.J Allergy Clin Immunol. 2002;109:1005–1011.

    Article  CAS  PubMed  Google Scholar 

  15. von Greyerz S, Zanni MP, Frutig K, Schnyder B, Burkhart C, Pichler WJ. Interaction of sulfonamide derivatives with the TCR of sulfamethoxazole-specific human alpha beta+T cell clones.J Immunol. 1999;162:595–602.

    Google Scholar 

  16. Zanni MP, Mauri-Hellweg D, Brander C, et al. Characterization of lidocaine-specific T cells.J Immunol. 1997;158:1139–1148.

    CAS  PubMed  Google Scholar 

  17. Kuechler PC, Britschgi M, Schmid S, Hari Y, Grabscheid B, Pichler WJ. Cytotoxic mechanisms in different forms of T-cell-mediated drug allergies.Allergy. 2004;59:613–622.

    Article  CAS  PubMed  Google Scholar 

  18. Schnyder B, Frutig K, Mauri-Hellweg D, Limat A, Yawalkar N, Pichler WJ. T-cell-mediated cytotoxicity against keratinocytes in sulfamethoxazol-induced skin reaction.Clin Exp Allergy. 1998;28:1412–1417.

    Article  CAS  PubMed  Google Scholar 

  19. Nassif A, Bensussan A, Boumsell L, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells.J Allergy Clin Immunol. 2004;114:1209–1215.

    Article  CAS  PubMed  Google Scholar 

  20. Nassif A, Bensussan A, Dorothee G, et al. Drug-specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis.J Invest Dermatol. 2002;118:728–733.

    Article  CAS  PubMed  Google Scholar 

  21. Landsteiner K, Jacobs J. Studies on the sensitisation of animals with simple chemical compounds.J Exp Med. 1935;61:643–656.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Park BK, Naisbitt DJ, Gordon SF, Kitteringham NR, Pirmohamed M. Metabolic activation in drug allergies.Toxicology. 2001;158:11–23.

    Article  CAS  PubMed  Google Scholar 

  23. Park BK, Tingle MD, Grabowski PS, Coleman JW, Kitteringham NR. Drug-protein conjugates, XI: disposition and immunogenicity of dinitrofluorobenzene, a model compound for the investigation of drugs as haptens.Biochem Pharmacol. 1987;36:591–599.

    Article  CAS  PubMed  Google Scholar 

  24. Weltzien HU, Moulon C, Martin S, Padovan E, Hartmann U, Kohler J. T cell immune responses to haptens: structural models for allergic and autoimmune reactions.Toxicology. 1996;107:141–151.

    Article  CAS  PubMed  Google Scholar 

  25. Dearman RJ, Hegarty JM, Kimber I. Inhalation exposure of mice to trimellitic anhydride induces both IgG and IgE anti-hapten antibody.Int Arch Allergy Appl Immunol. 1991;95:70–76.

    Article  CAS  PubMed  Google Scholar 

  26. Dearman RJ, Warbrick EV, Humphreys IR, Kimber I. Characterization in mice of the immunological properties of five allergenic acid anhydrides.J Appl Toxicol. 2000;20:221–230.

    Article  CAS  PubMed  Google Scholar 

  27. Doyle HA, Mamula MJ. Post-translational protein modifications in antigen recognition and autoimmunity.Trends Immunol. 2001;22:443–449.

    Article  CAS  PubMed  Google Scholar 

  28. Kimber I, Dearman RJ. Immunologic basis for autoimmunity and the potential influences of xenobiotics.Toxicol Lett. 2002;127:77–81.

    Article  CAS  PubMed  Google Scholar 

  29. Palmer JM, Robe AJ, Burt AD, Kirby JA, Jones DE. Covalent modification as a mechanism for the breakdown of immune tolerance to pyruvate dehydrogenase complex in the mouse.Hepatology. 2004;39:1583–1592.

    Article  CAS  PubMed  Google Scholar 

  30. Cribb AE, Spielberg SP, Griffin GP. N4-hydroxylation of sulfamethoxazole by cytochrome P450 of the cytochrome P4502c subfamily and reduction of sulfamethoxazole hydroxylamine in human and rat hepatic microsomes.Drug Metab Dispos. 1995;23:406–414.

    CAS  PubMed  Google Scholar 

  31. Gill HJ, Maggs JL, Madden S, Pirmohamed M, Park BK. The effect of fluconazole and ketoconazole on the metabolism of sulphamethoxazole.Br J Clin Pharmacol. 1996;42:347–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mitra AK, Thummel KE, Kalhorn TF, Kharasch ED, Unadkat JD, Slattery JT. Inhibition of sulfamethoxazole hydroxylamine formation by fluconazole in human an liver microsomes and healthy volunteers.Clin Pharmacol Ther. 1996;59:332–340.

    Article  CAS  PubMed  Google Scholar 

  33. van der Ven AJ, Mantel MA, Vree TB, Koopmans PP, van der Meer JW. Formation and elimination of sulphamethoxazole hydroxylamine after oral administration of sulphamethoxazole.Br J Clin Pharmacol. 1994;38:147–150.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Cribb AE, Miller M, Leeder JS, Hill J, Spielberg SP. Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione: implications for idiosyncratic toxicity.Drug Metab Dispos. 1991;19:900–906.

    CAS  PubMed  Google Scholar 

  35. Naisbitt DJ, O'Neill PM, Pirmohamed M, Park BK. Synthesis and reactions of nitroso sulphamethoxazole with biological nucleophiles: implications for immune mediated toxicity.Bioorg Med Chem Lett. 1996;6:1511–1516.

    Article  CAS  Google Scholar 

  36. Naisbitt DJ, Farrell J, Gordon SF, et al. Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation.Mol Pharmacol. 2002;62:628–637.

    Article  CAS  PubMed  Google Scholar 

  37. Kurian JR, Bajad SU, Miller JL, Chin NA, Trepanier LA. NADH cytochrome b5 reductase and cytochrome b5 catalyze the microsomal reduction of xenobiotic hydroxylamines and amidoximes in humans.J Pharmacol Exp Ther. 2004;311:1171–1178.

    Article  CAS  PubMed  Google Scholar 

  38. Naisbitt DJ, Vilar FJ, Stalford AC, Wilkins EG, Pirmohamed M, Park BK. Plasma cysteine deficiency and decreased reduction of nitrososulfamethoxazole with HIV infection.AIDS Res Hum Retroviruses. 2000;16:1929–1938.

    Article  CAS  PubMed  Google Scholar 

  39. Trepanier LA, Yoder AR, Bajad S, Beckwith MD, Bellehumeur JL, Graziano FM. Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection.J Acquir Immune Defic Syndr. 2004;36:1041–1050.

    Article  CAS  PubMed  Google Scholar 

  40. Walmsley SL, Winn LM, Harrison ML, Uetrecht JP, Wells PG. Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from HIV-infected patients: toxicological and pathological implications.AIDS. 1997;11:1689–1697.

    Article  CAS  PubMed  Google Scholar 

  41. Wijsman JA, Dekaban GA, Rieder MJ. Differential toxicity of reactive metabolites of clindamycin and sulfonamides in HIV-infected cells: influence of HIV infection on clindamycin toxicity in vitro.J Clin Pharmacol. 2005;45:346–351.

    Article  CAS  PubMed  Google Scholar 

  42. Pirmohamed M, Park BK. HIV and drug allergy.Curr Opin Allergy Clin Immunol. 2001;1:311–316.

    Article  CAS  PubMed  Google Scholar 

  43. Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation.J Immunol. 2005;174:4407–4414.

    Article  CAS  PubMed  Google Scholar 

  44. Eliaszewicz M, Flahault A, Roujeau JC, et al. Prospective evaluation of risk factors of cutaneous drug reactions to sulfonamides in patients with AIDS.J Am Acad Dermatol. 2002;47:40–46.

    Article  PubMed  Google Scholar 

  45. Manchanda T, Hess D, Dale L, Ferguson SG, Rieder MJ. Haptenation of sulfonamide reactive metabolites to cellular proteins.Mol Pharmacol. 2002;62:1011–1026.

    Article  CAS  PubMed  Google Scholar 

  46. Naisbitt DJ, Gordon SF, Pirmohamed M, et al. Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo.Br J Pharmacol. 2001;133:295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Naisbitt DJ, Hough SJ, Gill HJ, Pirmohamed M, Kitteringham NR, Park BK. Cellular disposition of sulphamethoxazole and its metabolites: implications for hypersensitivity.Br J Pharmacol. 1999;126:1393–1407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Reilly TP, Lash LH, Doll MA, Hein DW, Woster PM, Svensson CK. A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions.J Invest Dermatol. 2000;114:1164–1173.

    Article  CAS  PubMed  Google Scholar 

  49. Summan M, Cribb AE. Novel non-labile covalent binding of sulfamethoxazole reactive metabolites to cultured human lymphoid cells.Chem Biol Interact. 2002;142:155–173.

    Article  CAS  PubMed  Google Scholar 

  50. Burkhart C, von Greyerz S, Depta JP, et al. Influence of reduced glutathione on the proliferative response of sulfamethoxazole-specific and sulfamethoxazole-metabolite-specific human CD4+ T-cells.Br J Pharmacol. 2001;132:623–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schnyder B, Burkhart C, Schnyder-Frutig K, et al. Recognition of sulfamethoxazole and its reactive metabolites by drug-specific CD4+ T cells from allergic individuals.J Immunol. 2000;164:6647–6654.

    Article  CAS  PubMed  Google Scholar 

  52. Pichler WJ. Pharmacological iteraction, of drugs with antigen-specific immune receptors: the p-i concept.Curr Opin Allergy Clin Immunol. 2002;2:301–305.

    Article  PubMed  Google Scholar 

  53. Zanni MP, von Greyerz S, Schnyder B, et al. HLA-restricted, processing- and metabolism-independent pathway of drug recognition by human alpha beta T lymphocytes.J Clin Invest. 1998;102:1591–1598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Naisbitt DJ, Pirmohamed M, Park BK. Drug presentation to T cells.J Allergy Clin Immunol. 2005;115:876–877.

    Article  CAS  PubMed  Google Scholar 

  55. Engler OB, Strasser I, Naisbitt DJ, Cerny A, Pichler WJ. A chemically inert drug can stimulate T cells in vitro by their T cell receptor in non-sensitised individuals.Toxicology. 2004;197:47–56.

    Article  CAS  PubMed  Google Scholar 

  56. Matzinger P. Tolerance, danger, and the extended family.Annu Rev Immunol. 1994;12:991–1045.

    Article  CAS  PubMed  Google Scholar 

  57. Janeway CA Jr. The immune system evolved to discriminate infectious nonself from noninfectious self.Immunol Today. 1992;13:11–16.

    Article  CAS  PubMed  Google Scholar 

  58. Naisbitt DJ, Gordon SF, Pirmohamed M, Park BK. Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment.Drug Saf. 2000;23:483–507.

    Article  CAS  PubMed  Google Scholar 

  59. Appleman LJ, Boussiotis VA. T cell anergy and costimulation.Immunol Rev. 2003;192:161–180.

    Article  CAS  PubMed  Google Scholar 

  60. Gallucci S, Lolkema M, Matzinger P. Natural adjuvants: endogenous activators of dendritic cells.Nat Med. 1999;5:1249–1255.

    Article  CAS  PubMed  Google Scholar 

  61. Todryk SM, Melcher AA, Dalgleish AG, Vile RG. Heat shock proteins refine the danger theory.Immunology. 2000;99:334–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells.Nature. 2003;425:516–521.

    Article  CAS  PubMed  Google Scholar 

  63. Hong F, Sekhar KR, Freeman ML, Liebler DC. Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation.J Biol Chem. 2005;280:31768–31775.

    Article  CAS  PubMed  Google Scholar 

  64. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses.Nat Rev Immunol. 2004;4:469–478.

    Article  CAS  PubMed  Google Scholar 

  65. Kabe Y, Ando K, Hirao S, Yoshida M, Handa H. Redox regulation of NF-kappaB activation: distinct redox regulation between the cytoplasm and the nucleus.Antioxid Redox Signal. 2005;7:395–403.

    Article  CAS  PubMed  Google Scholar 

  66. Ardeshna KM, Pizzey AR, Devereux S, Khwaja A. The PI3 kinase, p38 SAP kinase and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells.Blood. 2000;96:1039–1046.

    CAS  PubMed  Google Scholar 

  67. Rescigno M, Martino M, Sutherland CL, Gold MR, Ricciardi-Castagnoli P. Dendritic cell survival and maturation are regulated by different signaling pathways.J Exp Med. 1998;188:2175–2180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system.Free Radic Biol Med. 2001;31:1287–1312.

    Article  CAS  PubMed  Google Scholar 

  69. Bruchhausen S, Zahn S, Valk E, Knop J, Becker D. Thiol antioxidants block the activation of antigen-presenting cells by contact sensitizers.J Invest Dermatol. 2003;121:1039–1044.

    Article  CAS  PubMed  Google Scholar 

  70. Mizuashi M, Ohtani T, Nakagawa S, Aiba S. Redox imbalance induced by contact sensitizers triggers the maturation of dendritic cells.J Invest Dermatol. 2005;124:579–586.

    Article  CAS  PubMed  Google Scholar 

  71. Aiba S, Terunuma A, Manome H, Tagami H. Dendritic cells differently respond to haptens and irritants by their production of cytokines and expression of co-stimulatory molecules.Eur J Immunol. 1997;27:3031–3038.

    Article  CAS  PubMed  Google Scholar 

  72. Coutant KD, de Fraissinette AB, Cordier A, Ulrich P. Modulation of the activity of human monocyte-derived dendritic cells by chemical haptens, a metal allergen, and a staphylococcal superantigen.Toxicol Sci. 1999;52:189–198.

    Article  CAS  PubMed  Google Scholar 

  73. Staquet MJ, Sportouch M, Jacquet C, Schmitt D, Guesnet J, Peguet-Navarro J Moderate skin sensitizers can induce phenotypic changes on in vitro generated dendritic cells.Toxicol In Vitro. 2004;17:493–500.

    Article  CAS  Google Scholar 

  74. Tuschl H, Kovac R, Weber E. The expression of surface markers on dendritic cells as indicators for the sensitizing potential of chemicals.Toxicol In Vitro. 2000;14:541–549.

    Article  CAS  PubMed  Google Scholar 

  75. Judge F, Boissier C, Rougier-Larzat N, et al. Regulation by allergens of chemokine receptor expression on in vitro-generated dendritic cells.Toxicology. 2005;212:227–238.

    Article  CAS  Google Scholar 

  76. Aiba S, Manome H, Nakagawa S, et al. p38 Mitogen-activated protein kinase and extracellular signal-regulated kinases play distinct roles in the activation of dendritic cells by two representative haptens, NiCl2 and 2,4-dinitrochlorobenzene.J Invest Dermatol. 2003;120:390–399.

    Article  CAS  PubMed  Google Scholar 

  77. Arrighi JF, Rebsamen M, Rousset F, Kindler V, Hauser C. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-alpha, and contact sensitizers.J Immunol. 2001;166:3837–3845.

    Article  CAS  PubMed  Google Scholar 

  78. Becker D, Valk E, Zahn S, Brand P, Knop J. Coupling of contact sensitizers to thiol groups is a key event for the activation of monocytes and nonocyte-derived dendritic cells.J Invest Dermatol. 2003;120:233–238.

    Article  CAS  PubMed  Google Scholar 

  79. Iijima N, Yanagawa Y, Onoe K. Role of early- or late-phase activation of p38 mitogen-activated protein kinae induced by tumour necrosis factor-alpha or 2,4-dinitrochlorobenzene during maturation of murine dendritic cells.Immunology. 2003;110:322–328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Aiba S, Manome H, Yoshino Y, Tagami H. In vitro treatment of human transforming growth factor-betal-treated monocyte-derived dendritic cells with haptens can induce the phenotypic and functional changes similar to epidermal Langerhans cells in the initiation phase of allergic contact sensitivity reaction.Immunology. 2000;101:68–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Manome H, Aiba S, Tagami H. Simple chemicals can induce maturation and apoptosis of dendritic cells.Immunology. 1999;98:481–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Aiba S, Katz SI. Phenotypic and functional characteristics of in vivo-activated Langerhans cells.J Immunol. 1990;145:2791–2796.

    CAS  PubMed  Google Scholar 

  83. Hulette BC, Ryan CA, Gildea LA, Gerberick GF. Relationship of CD86 surface marker expression and cytotoxicity on dendritic cells exposed to chemical allergen.Toxicol Appl Pharmacol. 2005;209:159–166.

    Article  CAS  PubMed  Google Scholar 

  84. Quezada SA, Jarvinen LZ, Lind EF, Noelle RJ. CD40/CD154 interactions at the interface of tolerance and immunity.Annu Rev Immunol. 2004;22:307–328.

    Article  CAS  PubMed  Google Scholar 

  85. Bour-Jordan H, Salomon BL, Thompson HL, Szot GL, Bernhard MR, Bluestone JA. Costimulation controls diabetes by altering the balance of pathogenic and regulatory T cells.J Clin Invest. 2004;114:979–987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pollard KM, Arnush M, Hultman P, Kono DH. Costimulation requirements of induced murine systemic autoimmune disease.J Immunol. 2004;173:5880–5887.

    Article  CAS  PubMed  Google Scholar 

  87. Carr A, Tindall B, Penny R, Cooper DA. In vitro cytotoxicity as a marker of hypersensitivity to sulphamethoxazole in patients with HIV.Clin Exp Immunol. 1993;94:21–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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;32:741–749.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Reilly TP 3rd, Bellevue FH 3rd, Woster PM, Svensson CK. Comparison of the in vitro cytotoxicity of hydroxylamine metabolites of sulfamethoxazole and dapsone.Biochem Pharmacol. 1998;55:803–810.

    Article  CAS  PubMed  Google Scholar 

  90. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk.J Clin Invest. 1988;82:1826–1832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gibson GG, Skett P.Introduction to Drug Metabolism. Cheltenham, UK: Nelson Thornes; 2001.

    Google Scholar 

  92. Baron JM, Holler D, Schiffer R, et al. Expression of multiple cytochrome p450 enzymes and multidrug resistance-associated transport proteins in human skin keratinocytes.J Invest Dermatol. 2001;116:541–548.

    Article  CAS  PubMed  Google Scholar 

  93. Du L, Hoffman SM, Keeney DS. Epidermal CYP2 family cytochromes P450.Toxicol Appl Pharmacol. 2004;195:278–287.

    Article  CAS  PubMed  Google Scholar 

  94. Krovat BC, Tracy JH, Omiecinski CJ. Fingerprinting of cytochrome P450 and microsomal epoxide hydrolase gene expression in human blood cells.Toxicol Sci. 2000;55:352–360.

    Article  CAS  PubMed  Google Scholar 

  95. Spencer DL, Masten SA, Lanier KM, et al. Quantitative analysis of constitutive and 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced cytochrome P450 1B1 expression in human lymphocytes.Cancer Epidemiol Biomarkers Prev. 1999;8:139–146.

    CAS  PubMed  Google Scholar 

  96. Sieben S, Baron JM, Blomeke B, Merk HF. Multiple cytochrome P450-isoenzymes mRNA are expressed in dendritic cells.Int Arch Allergy Immunol. 1999;118:358–361.

    Article  CAS  PubMed  Google Scholar 

  97. Norgauer J, Ibig Y, Gmeiner D, Herouy Y, Fiebich BL. Prostaglandin E2 synthesis in human monocyte-derived dendritic cells.Int J Mol Med. 2003;12:83–86.

    CAS  PubMed  Google Scholar 

  98. Scholz W, Platzer B, Schumich A, et al. Initial human myeloid/dendritic cell progenitors identified by absence of myeloperoxidase protein expression.Exp Hematol. 2004;32:270–276.

    Article  CAS  PubMed  Google Scholar 

  99. Saeki M, Saito Y, Nagano M, Teshima R, Ozawa S, Sawada J. mRNA expression of multiple cytochrome p450 isozymes in four types of cultured skin cells.Int Arch Allergy Immunol. 2002;127:333–336.

    Article  CAS  PubMed  Google Scholar 

  100. Cribb AE, Spielberg SP. Sulfamethoxazole is metabolized to the hydroxylamine in humans.Clin Pharmacol Ther. 1992;51:522–526.

    Article  CAS  PubMed  Google Scholar 

  101. Ju C, Uetrecht JP. Detection of 2-hydroxyiminostilbene in the urine of patients taking carbamazepine and its oxidation to a reactive iminoquinone intermediate.J Pharmacol Exp Ther. 1999;288:51–56.

    CAS  PubMed  Google Scholar 

  102. Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro.Biochem Pharmacol. 1992;43:1675–1682.

    Article  CAS  PubMed  Google Scholar 

  103. Cuttle L, Munns AJ, Hogg NA, et al. Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation.Drug Metab Dispos. 2000;28:945–950.

    CAS  PubMed  Google Scholar 

  104. Walsh JS, Reese MJ, Thurmond LM. The metabolic activation of abacavir by human liver cytosol and expressed human alcohol dehydrogenase isozymes.Chem Biol Interact. 2002;142:135–154.

    Article  CAS  PubMed  Google Scholar 

  105. Njoku D 2nd, Laster MJ 2nd, Gong DH 2nd, Eger EI 2nd, Reed GF, Martin JL. Biotransformation of halothane, enflurane, isoflurane, and desflurane to trifluoroacetylated liver proteins: association between protein acylation and hepatic injury.Anesth Analg. 1997;84:173–178.

    Article  CAS  PubMed  Google Scholar 

  106. Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. The role of metabolic activation in drug-induced hepatotoxicity.Annu Rev Pharmacol Toxicol. 2005;45:177–202.

    Article  CAS  PubMed  Google Scholar 

  107. Ju C, Pohl LR. Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions.Toxicology. 2005;209:109–112.

    Article  CAS  PubMed  Google Scholar 

  108. French LE, Tschopp J. Constitutive Fas ligand expression in several non-lymphoid mouse tissues: implications for immune-protection and cell turnover.Behring Inst Mitt. 1996;97:156–160.

    CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  110. Eliasson E, Gardner I, Hume-Smith H, de Waziers I, Beaune P, Kenna JG. Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis.Chem Biol Interact. 1998;116:123–141.

    Article  CAS  PubMed  Google Scholar 

  111. Cohen EN, Trudell JR, Edmunds HN, Watson E. Urinary metabolites of halothane in man.Anesthesiology. 1975;43:392–401.

    Article  CAS  PubMed  Google Scholar 

  112. Kenna JG, Satoh H, Christ DD, Pohl LR. Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane.J Pharmacol Exp Ther. 1988;245:1103–1109.

    CAS  PubMed  Google Scholar 

  113. Gut J, Christen U, Huwyler J. Mechanisms of halothane toxicity: novel insights.Pharmacol Ther. 1993;58:133–155.

    Article  CAS  PubMed  Google Scholar 

  114. 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;8:1635–1641.

    Article  CAS  PubMed  Google Scholar 

  115. Mieli-Vergani G, Vergani D, Tredger JM, Eddleston AL, Davis M, Williams R. Lymphocyte cytotoxicity to halothane altered hepatocytes in patients with severe hepatic necrosis following halothane anaesthesia.J Clin Lab Immunol. 1980;4:49–51.

    CAS  PubMed  Google Scholar 

  116. Furst SM, Gandolfi AJ. Interaction of lymphocytes with Kupffer cells from halothane-exposed guinea pigs.Int Arch Allergy Immunol. 1997;114:46–53.

    Article  CAS  PubMed  Google Scholar 

  117. Furst SM, Luedke D, Gaw HH, Reich R, Gandolfi AJ. Demonstration of a cellular immune response in halothane-exposed guinea pigs.Toxicol Appl Pharmacol. 1997;143:245–255.

    Article  CAS  PubMed  Google Scholar 

  118. Swanson HI. Cytochrome P450 expression in human keratinocytes: an aryl hydrocarbon receptor perspective.Chem Biol Interact. 2004;149:69–79.

    Article  CAS  PubMed  Google Scholar 

  119. Yengi LG, Xiang Q, Pan J, et al. Quantitation of cytochrome P450 mRNA levels in human skin.Anal Biochem. 2003;316:103–110.

    Article  CAS  PubMed  Google Scholar 

  120. Roychowdhury S, Vyas PM, Reilly TP, Gaspari AA, Svensson CK. Characterization of the formation and localization of sulfamethoxazole and dapsone-associated drug-protein adducts in human epidermal keratinocytes.J Pharmacol Exp Ther. 2005;314:43–52.

    Article  CAS  PubMed  Google Scholar 

  121. Dey A, Parmar D, Dayal M, Dhawan A, Seth PK. Cytochrome P450 1A1 (CYP1A1) in blood lymphocytes evidence for catalytic activity and mRNA expression.Life Sci. 2001;69:383–393.

    Article  CAS  PubMed  Google Scholar 

  122. McConnachie LA, Phillips B, Bajpai M, Shen DD, Ho RJ. Only truncated, not complete cytochrome p450 2D6 RNA transcript and no detectable enzyme activity are expressed in human lymphocytes.Drug Metab Dispos. 2003;31:1103–1107.

    Article  CAS  PubMed  Google Scholar 

  123. Starkel P, Sempoux C, Van Den Berge V, et al. CYP 3A proteins are expressed in human neutrophils and lymphocytes but are not induced by rifampicin.Life Sci. 1999;64:643–653.

    Article  CAS  PubMed  Google Scholar 

  124. Finnstrom N, Ask B, Dahl ML, Gadd M, Rane A. Intra-individual variation and sex differences in gene expression of cytochromes P450 in circulating leukocytes.Pharmacogenomics J. 2002;2:111–116.

    Article  CAS  PubMed  Google Scholar 

  125. Baron JM, Zwadlo-Klarwasser G, Jugert F, et al. Cytochrome P450 1B1: a major P450 isoenzyme in human blood monocytes and macrophage subsets.Biochem Pharmacol. 1998;56:1105–1110.

    Article  CAS  PubMed  Google Scholar 

  126. Shimada T, Gillam EM, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H. Oxidation of xenobiotics by recombinant human cytochrome P450 1B1.Drug Metab Dispos. 1997;25:617–622.

    CAS  PubMed  Google Scholar 

  127. Hofstra AH, Uetrecht JP. Myeloperoxidase-mediated activation of xenobiotics by human leukocytes.Toxicology. 1993;82:221–242.

    Article  CAS  PubMed  Google Scholar 

  128. Vogel C. Prostaglandin H synthases and their importance in chemical toxicity.Curr Drug Metab. 2000;1:391–404.

    Article  CAS  PubMed  Google Scholar 

  129. Cribb AE, Miller M, Tesoro A, Spielberg SP. Peroxidase-dependent oxidation of sulfonamides by monocytes and neutrophils from humans and dogs.Mol Pharmacol. 1990;38:744–751.

    CAS  PubMed  Google Scholar 

  130. Uetrecht JP, Shear NH, Zahid N. N-chlorination of sulfamethoxazole and dapsone by the myeloperoxidase system.Drug Metab Dispos. 1993;21:830–834.

    CAS  PubMed  Google Scholar 

  131. Furst SM, Uetrecht JP. Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils.Biochem Pharmacol. 1993;45:1267–1275.

    Article  CAS  PubMed  Google Scholar 

  132. Lai WG, Zahid N, Uetrecht JP. Metabolism of trimethoprim to a reactive iminoquinone methide by activated human neutrophils and hepatic microsomes.J Pharmacol Exp Ther. 1999;291:292–299.

    CAS  PubMed  Google Scholar 

  133. Rubin RL, Kretz-Rommel A. Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions.Curr Opin Hematol. 2001;8:35.

    Article  Google Scholar 

  134. Jiang X, Khursigara G, Rubin RL. Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils.Science. 1994;266:810–813.

    Article  CAS  PubMed  Google Scholar 

  135. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies.Arthritis Rheum. 2000;43:405–413.

    Article  CAS  PubMed  Google Scholar 

  136. Wiik A, Brimnes J, Heegaard NH. Distinct differences in autoantigen specificity of anti-neutrophil cytoplasm antibodies in systemic vasculitides and other inflammatory diseases.Isr Med Assoc J. 1999;1:4–7.

    CAS  PubMed  Google Scholar 

  137. Ujihara M, Horiguchi Y, Ikai K, Urade Y. Characterization and distribution of prostaglandin D synthetase in rat skin.J Invest Dermatol. 1988;90:448–451.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dean J. Naisbitt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sanderson, J.P., Naisbitt, D.J. & Park, B.K. Role of bioactivation in drug-induced hypersensitivity reactions. AAPS J 8, 7 (2006). https://doi.org/10.1208/aapsj080107

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/aapsj080107

Keywords

Navigation