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Research ArticleArticle

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

Linling Cheng, Benjamin J. Stewart, Qiang You, Dennis R. Petersen, Joseph A. Ware, Joseph R. Piccotti, Thomas T. Kawabata and Cynthia Ju
Molecular Pharmacology June 2008, 73 (6) 1769-1775; DOI: https://doi.org/10.1124/mol.107.043273
Linling Cheng
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Benjamin J. Stewart
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Qiang You
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Dennis R. Petersen
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Joseph A. Ware
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Joseph R. Piccotti
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Thomas T. Kawabata
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Cynthia Ju
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Abstract

Immune-mediated drug hypersensitivity reactions (IDHRs) represent a significant problem due to their unpredictable and severe nature, as well as the lack of understanding of the pathogenesis. Sulfamethoxazole (SMX), a widely used antibiotic, has been used as a model compound to investigate the underlying mechanism of IDHRs because it has been associated with a relatively high incidence of hypersensitivity. Previous studies by others showed that administration of 4-(nitroso)-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide (SMX-NO), the reactive metabolite of SMX, to rats resulted in the generation of SMX-specific antibodies and ex vivo splenocyte proliferative responses, as well as haptenation of skin keratinocytes, circulating peripheral blood mononuclear cells, and splenocytes. The objective of the present study was to further investigate SMX-NO-protein binding in relationship to its immunogenicity. In female DBA/1 mice treated with SMX-NO, varying degrees of SMX-NO-dependent T-cell responses and SMX-NO-protein adduct formation were observed in the spleen and in inguinal, brachial, and axillary lymph nodes. The data suggested a tissue-specific threshold of SMX-NO dosage that triggers the detection of adducts and immune response. Furthermore, serum albumin and immunoglobulin were identified as protein targets for SMX-NO modification. It seemed that these adducts were formed in the blood, circulated to lymphoid tissues, and initiated SMX-NO-dependent immune responses. Collectively, these data revealed a causal link between the deposition of SMX-NO-protein adducts in a lymphoid tissue and the induction of immune response in that tissue. Our findings also suggest that the immunogenicity of SMX-NO is determined by the immunogenic nature of the hapten, rather than special characteristics of the adducted protein.

Footnotes

  • This work was supported by Pfizer Global Research and Development funds (to C.J.).

  • ABBREVIATIONS: IDHR, immune-mediated drug hypersensitivity reaction; SMX, sulfamethoxazole; SMX-NO, 4-(nitroso)-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide; MSA, mouse serum albumin; KLH, keyhole limpet hemocyanin; DMEM, Dulbecco's modified Eagle's medium; CFA, complete Freund's adjuvant; IFA, incomplete Freund's adjuvant; ILN, inguinal lymph node(s); FCS, fetal calf serum; LC, liquid chromatography; MS/MS, tandem mass spectrometry; IACD, iodoacetamide.

    • Received November 7, 2007.
    • Accepted March 10, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

Linling Cheng, Benjamin J. Stewart, Qiang You, Dennis R. Petersen, Joseph A. Ware, Joseph R. Piccotti, Thomas T. Kawabata and Cynthia Ju
Molecular Pharmacology June 1, 2008, 73 (6) 1769-1775; DOI: https://doi.org/10.1124/mol.107.043273

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Research ArticleArticle

Covalent Binding of the Nitroso Metabolite of Sulfamethoxazole Is Important in Induction of Drug-Specific T-Cell Responses in Vivo

Linling Cheng, Benjamin J. Stewart, Qiang You, Dennis R. Petersen, Joseph A. Ware, Joseph R. Piccotti, Thomas T. Kawabata and Cynthia Ju
Molecular Pharmacology June 1, 2008, 73 (6) 1769-1775; DOI: https://doi.org/10.1124/mol.107.043273
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