Abstract
Bioactivation of sulfonamides and the subsequent formation of haptenated proteins is believed to be a critical step in the development of hypersensitivity reactions to these drugs. Numerous lines of evidence suggest that the presence of such adducts in dendritic cells (DCs) migrating to draining lymph nodes is essential for the development of cutaneous reactions to xenobiotics. Our objective was to determine the ability of human DCs to form drug-protein covalent adducts when exposed to sulfamethoxazole (SMX), dapsone (DDS), or their arylhydroxylamine metabolites [sulfamethoxazole hydroxylamine (S-NOH) and dapsone hydroxylamine (D-NOH)] and to take up preformed adduct. Naive and immature CD34+ KG-1 cells were incubated with SMX, DDS, or metabolites. Formation of haptenated proteins was probed using confocal microscopy and ELISA. Cells were also incubated with preformed adduct (drug-bovine serum albumin conjugate), and uptake was determined using confocal microscopy. Both naive and immature KG-1 cells were able to bioactivate DDS, forming drug-protein adducts, whereas cells showed very little protein haptenation when exposed to SMX. Exposure to S-NOH or D-NOH resulted in protein haptenation in both cell types. Both immature and naive KG-1 cells were able to take up preformed haptenated proteins. Thus, DCs may acquire haptenated proteins associated with drugs via intracellular bioactivation, uptake of reactive metabolites, or uptake of adduct formed and released by adjacent cells (e.g., keratinocytes).
Footnotes
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This work was supported in part by National Institutes of Health Grants AI41395 and GM63821 (to C.K.S.).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.013680.
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ABBREVIATIONS: CDR, cutaneous drug reaction; APC, antigen presenting cell; LC, Langerhans cell; DC, dendritic cell; DDS, dapsone; SMX, sulfamethoxazole; D-NOH, dapsone hydroxylamine; S-NOH, sulfamethoxazole hydroxylamine; ELISA, enzyme-linked immunosorbent assay; HLA, human leukocyte antigen; FMO, flavin monooxygenase; MMZ, methimazole; ABH, 4-aminobenzoic acid hydrazide; rh, recombinant human; IL, interleukin; GM-CSF, granulocyte macrophage–colony-stimulating factor; PBS, phosphate-buffered saline; BSA, bovine serum albumin.
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↵1 Current affiliation: Department of Pathobiology / NC22, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195
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↵2 Current affiliation: Riley Hospital for Children, Wells Center for Pediatric Research, 1044 West Walnut, R4 Room W344, Indianapolis, IN 46202
- Received November 3, 2006.
- Accepted January 9, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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