Novel non-labile covalent binding of sulfamethoxazole reactive metabolites to cultured human lymphoid cells

Summan, Mukesh; Cribb, Alastair E.

doi:10.1016/s0009-2797(02)00060-1

Cited by 38 publications

(29 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RNeasy 96 total RNA extraction kit and RLT lysis buffer were obtained from Qiagen. Oligo(dT) [12][13][14][15][16][17][18] primer, 2Ј-deoxynucleoside 5Ј-triphosphate mix and the Superscript II reverse transcriptase kit were obtained from Invitrogen Life Technologies. Oligonucleotide fluorogenic probes and TaqMan Universal PCR Mastermix were obtained from Applied Biosystems.…”

Section: Methodsmentioning

confidence: 99%

“…1) (3,12). SMX-NO can bind covalently to cysteine residues on cellular protein (4,(13)(14)(15)(16) and this binding, above a threshold, causes direct toxicity (5,16) but also provides an antigenic signal to SMX-NO-specific T cells (9,17). Furthermore, Ag-specific T cells have been isolated and cloned from hypersensitive patients and have been characterized in terms of their functionality and phenotype (6 -8, 18, 19).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

Sanderson

Naisbitt

Farrell

et al. 2007

The Journal of Immunology

117

107

View full text Add to dashboard Cite

Different signals in addition to the antigenic signal are required to initiate an immunological reaction. In the context of sulfamethoxazole allergy, the Ag is thought to be derived from its toxic nitroso metabolite, but little is known about the costimulatory signals, including those associated with dendritic cell maturation. In this study, we demonstrate increased CD40 expression, but not CD80, CD83, or CD86, with dendritic cell surfaces exposed to sulfamethoxazole (250–500 μM) and the protein-reactive metabolite nitroso sulfamethoxazole (1–10 μM). Increased CD40 expression was not associated with apoptosis or necrosis, or glutathione depletion. Covalently modified intracellular proteins were detected when sulfamethoxazole was incubated with dendritic cells. Importantly, the enzyme inhibitor 1-aminobenzotriazole prevented the increase in CD40 expression with sulfamethoxazole, but not with nitroso sulfamethoxazole or LPS. The enzymes CYP2C9, CYP2C8, and myeloperoxidase catalyzed the conversion of sulfamethoxazole to sulfamethoxazole hydroxylamine. Myeloperoxidase was expressed at high levels in dendritic cells. Nitroso sulfamethoxazole immunogenicity was inhibited in mice with a blocking anti-CD40L Ab. In addition, when a primary nitroso sulfamethoxazole-specific T cell response using drug-naive human cells was generated, the magnitude of the response was enhanced when cultures were exposed to a stimulatory anti-CD40 Ab. Finally, increased CD40 expression was 5-fold higher on nitroso sulfamethoxazole-treated dendritic cells from an HIV-positive allergic patient compared with volunteers. These data provide evidence of a link between localized metabolism, dendritic cell activation, and drug immunogenicity.

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

Sanderson

Naisbitt

Farrell

et al. 2007

The Journal of Immunology

117

107

View full text Add to dashboard Cite

show abstract

“…NADH cytochrome (Kurian et al, 2004;Sacco and Trepanier, 2010), potentially restricting the formation of sulfonamide-derived protein adducts and direct sulfonamide toxicity. However, oxidation of SMX hydroxylamine occurs spontaneously, generating nitroso SMX, which has been shown to modify selective cysteine residues expressed on both cellular and extracellular protein (Naisbitt et al, 1999(Naisbitt et al, , 2002Manchanda et al, 2002;Summan and Cribb, 2002;Callan et al, 2009;Eyanagi et al, 2012 ). Modification of cell surface proteins on immune cells occurs rapidly; protein conjugates are then internalized via caveolae-dependent endocytosis (Manchanda et al, 2002;Elsheikh et al, 2010).…”

Section: The Antigenicity and Immunogenicity Of Drugs That Acquirementioning

confidence: 99%

Idiosyncratic Adverse Drug Reactions: Current Concepts

2013

View full text Add to dashboard Cite

“…The hapten hypothesis predicts that a chemically reactive metabolite is generated and binds to endogenous proteins, and the drug-protein adduct serves as the antigen. In SMX, its oxidative metabolite, SMX-NO, has been identified as the protein-reactive intermediate (Naisbitt et al, 1999Reilly et al, 2000;Manchanda et al, 2002;Summan and Cribb, 2002). It has been demonstrated that administration of SMX-NO, but not SMX, resulted in cell surface haptenation of skin keratinocytes, circulating peripheral blood mononuclear cells, and splenocytes .…”

mentioning

confidence: 99%

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

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

Novel non-labile covalent binding of sulfamethoxazole reactive metabolites to cultured human lymphoid cells

Cited by 38 publications

References 27 publications

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

Sulfamethoxazole and Its Metabolite Nitroso Sulfamethoxazole Stimulate Dendritic Cell Costimulatory Signaling

Idiosyncratic Adverse Drug Reactions: Current Concepts

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

Contact Info

Product

Resources

About