Roles of endogenous ascorbate and glutathione in the cellular reduction and cytotoxicity of sulfamethoxazole-nitroso

Lavergne, Sidonie N.; Kurian, Joseph R.; Bajad, Sunil; Maki, Jennifer E.; Yoder, Andrea R.; Guzinski, M. V.; Graziano, Frank M.; Trepanier, Lauren A.

doi:10.1016/j.tox.2006.01.018

Cited by 29 publications

(40 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To generate an anti-SMX Ab for immunochemical detection of SMX protein adducts, SMX was conjugated to human serum albumin (for use as a positive control for the validation of the ELISA protocol), and to keyhole limpet hemocyanin for use as a soluble Ag for rabbit immunization, using a previously described procedure (27). Drug-protein conjugation was confirmed by spectrophotometry, as well as by reactivity with rabbit anti-SMX Ab, kindly provided by Dr. Michael Rieder (London, ON, Canada).…”

Section: Reagents and Chemicalsmentioning

confidence: 99%

“…The rabbit immunization against SMX-keyhole limpet hemocyanin was approved by an Institutional Animal Care and Use Committee, under a U.S. Department of Agriculture license (#35-B-0097 and 36-R-0108) and a Public Health Service accreditation (#A4284-01) (Panigen, Branchardville, WI) (27). The reactivity of anti-sera against SMX-human serum albumin was confirmed by ELISA and immunoblotting.…”

Section: Reagents and Chemicalsmentioning

confidence: 99%

See 1 more Smart Citation

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Elsheikh

Lavergne

Castrejón-Flores

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Recognition of drugs by immune cells is usually explained by the hapten model, which states that endogenous metabolites bind irreversibly to protein to stimulate immune cells. Synthetic metabolites interact directly with protein generating antigenic determinants for T-cells; however, experimental evidence relating intracellular metabolism in immune cells and the generation of physiologically relevant antigens to functional immune responses is lacking. The aim of this study was to develop an integrated approach using both animal and human experimental systems to characterize sulfamethoxazole (SMX) metabolism-derived antigenic protein adduct formation in immune cells and define the relationship between adduct formation, cell death, co-stimulatory signalling and stimulation of a T-cell response. Formation of SMX-derived adducts in antigen presenting cells was dose- and time-dependent, detectable at non-toxic concentrations and dependent on drug metabolizing enzyme activity. Adduct formation above a threshold induced necrotic cell death, dendritic cell co-stimulatory molecule expression and cytokine secretion. Antigen presenting cells cultured with SMX for 16h, the time needed for drug metabolism, stimulated T-cells from sensitized mice and lymphocytes and T-cell clones from allergic patients. Enzyme inhibition decreased SMX-derived protein adduct formation and the T-cell response. Dendritic cells cultured with SMX and adoptively transferred to recipient mice initiated an immune response; however, T-cells were stimulated with adducts derived from SMX metabolism in antigen presenting cells, not the parent drug. This study shows that antigen presenting cells metabolize SMX; subsequent protein binding generates a functional T-cell antigen. Adduct formation above a threshold stimulates cell death, which provides a maturation signal for dendritic cells.

show abstract

Section: Reagents and Chemicalsmentioning

confidence: 99%

Section: Reagents and Chemicalsmentioning

confidence: 99%

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Elsheikh

Lavergne

Castrejón-Flores

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Sulfamethoxazole is also acetylated by N-acetyltransferase into sulfamethoxazole-N-acetyl, which increases its solubility. The renal excretion of sulfamethoxazole-N-acetyl is the major pathway of sulfamethoxazole removal (17,18).…”

mentioning

confidence: 99%

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis

Alsaad

Dijkstra

Akkerman

et al. 2016

Antimicrob Agents Chemother

View full text Add to dashboard Cite

g For treatment of multidrug-resistant tuberculosis (MDR-TB), there is a scarcity of antituberculosis drugs. Co-trimoxazole is one of the available drug candidates, and it is already frequently coprescribed for TB-HIV-coinfected patients. However, only limited data are available on the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of co-trimoxazole in TB patients. The objective of this study was to evaluate the PK parameters and in vitro PD data on the effective part of co-trimoxazole: sulfamethoxazole. In a prospective PK study in patients infected with drug-susceptible Mycobacterium tuberculosis (drug-susceptible TB patients) (age, >18), sulfamethoxazole-trimethoprim (SXT) was administered orally at a dose of 960 mg once daily. Onecompartment population pharmacokinetic modeling was performed using

show abstract

“…This is believed to be an idiosyncratic consequence of enzymatic generation of the hydroxylamine metabolite (SMX hydroxylamine; SMX-NHOH) and subsequent autoxidation to a protein-reactive nitroso species (Cribb et al, 1991). The cellular distribution (Naisbitt et al, 1999), cytotoxicity (Vyas et al, 2005;Lavergne et al, 2006), and immunogenicity (Naisbitt et al, 2001) of SMX metabolites have been studied extensively.SMX-NHOH formation has been found both in hepatic microsomes (Cribb and Spielberg, 1990a;Cribb et al, 1995) and in vivo (Cribb and Spielberg, 1992;Gill et al, 1996). Metabolism of SMX to SMX-NHOH is catalyzed by human hepatic CYP2C9 (Cribb et al, 1995;Gill et al, 1999) and neutrophilic myeloperoxidase (Cribb et al, 1990).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Nonenzymatic Formation of a Novel Hydroxylated Sulfamethoxazole Derivative in Human Liver Microsomes: Implications for Bioanalysis of Sulfamethoxazole Metabolites

Sanderson

Hollis²,

Maggs³

et al. 2008

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Sulfamethoxazole is metabolized by microsomal CYP2C9 to a hydroxylamine that is thought to be responsible for the relatively high incidence of hypersensitivity reactions associated with the drug. Accurate quantification of the hydroxylamine requires the loss of metabolite through autoxidation to be blocked with ascorbate. In this study, a partly nonenzymatically generated arylhydroxylated derivative of sulfamethoxazole was identified by liquid chromatography/mass spectrometry in incubations of human liver microsomes, and it was found to coelute with the isomeric hydroxylamine under the conditions of three published highperformance liquid chromatography (HPLC) assays. Partial inhibition of the aryl hydroxylation by 1-aminobenzotriazole suggested some involvement of cytochrome P450. However, the formation of this compound was ascorbate-dependent, and it was enhanced by the addition of Fe 2؉ /EDTA and inhibited by desferrioxamine but not by mannitol. These findings are consistent with the phenol being generated via an Fe 2؉ /ascorbate/O 2 -oxygenating system that does not involve hydroxyl radicals. It was also produced by H 2 O 2 / ascorbate. Because the compound shares close chromatographic similarities with the hydroxylamine metabolite, it is possible that previous studies may have inaccurately characterized or quantified sulfamethoxazole metabolism.The antimicrobial sulfamethoxazole (SMX) (Fig. 1) is associated with a relatively high incidence of immune-mediated hypersensitivity reactions (Vilar et al., 2003). This is believed to be an idiosyncratic consequence of enzymatic generation of the hydroxylamine metabolite (SMX hydroxylamine; SMX-NHOH) and subsequent autoxidation to a protein-reactive nitroso species (Cribb et al., 1991). The cellular distribution (Naisbitt et al., 1999), cytotoxicity (Vyas et al., 2005;Lavergne et al., 2006), and immunogenicity (Naisbitt et al., 2001) of SMX metabolites have been studied extensively.SMX-NHOH formation has been found both in hepatic microsomes (Cribb and Spielberg, 1990a;Cribb et al., 1995) and in vivo (Cribb and Spielberg, 1992;Gill et al., 1996). Metabolism of SMX to SMX-NHOH is catalyzed by human hepatic CYP2C9 (Cribb et al., 1995;Gill et al., 1999) and neutrophilic myeloperoxidase (Cribb et al., 1990). Although it was claimed that cyclooxygenase could also N-hydroxylate SMX, a recent study found that the oxidation of SMX in cyclooxygenase incubations containing ascorbate was due to H 2 O 2 in the reaction mixture (Vyas et al., 2006). It is noteworthy that, in the context of the present observations, accurate quantification of a hydroxylamine in vitro (Cribb and Spielberg, 1990a) and in vivo (Gill et al., 1996;Winter et al., 2004) requires the loss of analyte through autoxidation to be blocked with a reducing agent; ascorbate being the agent of choice. In addition, identification of the hydroxylamine has often depended upon cochromatography with an authentic standard using relatively simple high-performance liquid chromatography (HPLC) conditions.In this st...

show abstract

Roles of endogenous ascorbate and glutathione in the cellular reduction and cytotoxicity of sulfamethoxazole-nitroso

Cited by 29 publications

References 42 publications

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Drug Antigenicity, Immunogenicity, and Costimulatory Signaling: Evidence for Formation of a Functional Antigen through Immune Cell Metabolism

Pharmacokinetic Evaluation of Sulfamethoxazole at 800 Milligrams Once Daily in the Treatment of Tuberculosis

Nonenzymatic Formation of a Novel Hydroxylated Sulfamethoxazole Derivative in Human Liver Microsomes: Implications for Bioanalysis of Sulfamethoxazole Metabolites

Contact Info

Product

Resources

About