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

Journal Article · Fri Sep 01 04:00:00 EDT 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.02.006· OSTI ID:20850403

Bhaiya, Payal ^[1]; Roychowdhury, Sanjoy ^[1]; Vyas, Piyush M ^[1]; Doll, Mark A ^[2]; Hein, David W ^[2]; Svensson, Craig K ^[1]

---

1. Division of Pharmaceutics, College of Pharmacy, University of Iowa, 115 S. Grand Avenue, S213 PHAR, Iowa City, IA 52242 (United States)
2. Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292 (United States)

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 was detected. 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.

• OSTI ID: 20850403
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 215; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ASCORBIC ACID
BIOLOGICAL STRESS
ENZYME IMMUNOASSAY
ENZYMES
FIBROBLASTS
GLUTATHIONE
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
HYDROXYLAMINE
LEAD SULFIDES
METABOLITES
MICROSCOPY
OXYGEN
PABA
PHOSPHATES
SULFONAMIDES
TOXICITY