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First published on January 12, 2007; DOI: 10.1124/dmd.106.013680

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Received for publication November 6, 2006.
Revised January 6, 2007.
Accepted for publication January 9, 2007.

Formation and Uptake of Arylhydroxylamine-Haptenated Proteins in Human Dendritic Cells

Sanjoy Roychowdhury 1, Piyush M. Vyas 2, Craig K. Svensson 3*

1 The Cleveland Clnic 2 Riley Hospital for Children 3 Purdue University

* Address correspondence to: E-mail: svensson{at}purdue.edu

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 (S-NOH, D-NOH) and to take up pre-formed 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 pre-formed adduct (Drug-BSA conjugate) and uptake determined using confocal microscopy. Both naive and immature KG-1 cells were able to bioactivate DDS forming drug-protein adducts, while 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 pre-formed 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).


Key words: flavin-containing monooxygenase, hypersensitivity, immunotoxicology, reactive metabolites, toxicology


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