Mechanistic perspectives on sulfonamide-induced cutaneous drug reactions

Reilly, Timothy P.; Ju, Changqing

doi:10.1097/00130832-200208000-00004

Cited by 34 publications

(14 citation statements)

References 89 publications

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“…Since most drug molecules are not highly reactive, bioactivation to reactive species appears to be an essential step in the initiation of immune reactions to these drugs. For sulfonamides in particular, it has been proposed that the formation of arylhydroxylamine metabolites is a determining factor in the CDRs associated with these drugs (Reilly and Ju, 2002;Svensson, 2003).…”

Section: Discussionmentioning

confidence: 99%

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bhaiya

Roychowdhury

Vyas

et al. 2006

Toxicology and Applied Pharmacology

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Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein were detectable. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone, DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time-and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.

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Section: Discussionmentioning

confidence: 99%

Bioactivation, protein haptenation, and toxicity of sulfamethoxazole and dapsone in normal human dermal fibroblasts☆

Bhaiya

Roychowdhury

Vyas

et al. 2006

Toxicology and Applied Pharmacology

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“…Sulfamethoxazole hydroxylamine is a reactive metabolite and may spontaneously form nitrosulfamethoxazole [101]. It has been shown that the nitroso metabolite binds covalently to host proteins, causing direct cellular toxicity, and that this necrotic cell death may provide a 'danger signal' to sensitized T-cells leading to the cascade of immune response and cytokine release manifesting as drug hypersensitivity [102].…”

Section: Drugs For Opportunistic Infectionsmentioning

confidence: 99%

Hypersensitivity reactions to HIV therapy

Chaponda

Pirmohamed

2011

Brit J Clinical Pharma

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Many drugs used for the treatment of HIV disease (including the associated opportunistic infections) can cause drug hypersensitivity reactions, which vary in severity, clinical manifestations and frequency. These reactions are not only seen with the older compounds, but also with the newer more recently introduced drugs. The pathogenesis is unclear in most cases, but there is increasing evidence to support that many of these are mediated through a combination of immunologic and genetic factors through the major histocompatibility complex (MHC). Genetic predisposition to the occurrence of these allergic reactions has been shown for some of the drugs, notably abacavir hypersensitivity which is strongly associated with the class I MHC allele, HLA-B*5701. Testing before the prescription of abacavir has been shown to be of clinical utility, has resulted in a change in the drug label, is now recommended in clinical guidelines and is practiced in most Western countries. For most other drugs, however, there are no good methods of prevention, and clinical monitoring with appropriate (usually supportive and symptomatic) treatment is required. There is a need to undertake further research in this area to increase our understanding of the mechanisms, which may lead to better preventive strategies through the development of predictive genetic biomarkers or through guiding the design of drugs less likely to cause these types of adverse drug reactions.

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“…Many of these cutaneous drug reactions are observed 7 days after drug initiation, suggesting idiosyncratic, delayed hypersensitivity reactions. 8 Risk factors include higher CD4 1 T-cell count >20 3 10 6 cells/L, 9 CD4:CD8 ratio <0.10, treatment for less than 14 days, 10 and possibly a slow acetylation phenotype. 11 Male sex, higher CD4 1 T-cell percentage, a history of syphilis, and a higher total protein are also associated with cutaneous reactions to TMP-SMX.…”

Section: Hypersensitivity To Trimethoprim-sulfamethoxazolementioning

confidence: 99%

“…Lymphocytes from immunocompetent patients with a history of TMP-SMX hypersensitivity display higher sulfamethoxazole cytotoxicity than those of control subjects. 8,16 Desensitization Several desensitization protocols have been developed for use in both adults and children with TMP-SMX hypersensitivity. Drug desensitization is defined as the conversion of a state of drug hypersensitivity to a nonreactive state by the cautious introduction of increasing amounts of antigen at regular time intervals over a relatively short period (4-6 hours).…”

Section: Pathogenesismentioning

confidence: 99%