Evaluation of intracellular ascorbate deficiency and the cytotoxicity of sulfamethoxazole nitroso in healthy and HIV-infected subjects

• Published in: Clinical pharmacology and therapeutics 2004-02, Vol.75 (2), p.P15-P15
• Main Authors: Trepanier, L. A., Guzinski, M. V., Maki, J. E., Yoder, A. R., Bajad, S., Bellehumeur, J. L., Beckwith, M. D., Graziano, F. M.
• Format: Article
• Language: English
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1016/j.clpt.2003.11.056

Sulfamethoxazole (SMX) hypersensitivity affects 20–50% of treated HIV patients. SMX‐nitroso (SMX‐NO), the cytotoxic metabolite thought to mediate these reactions, is non‐enzymatically reduced by ascorbate (AA). The purpose of these studies was to determine the relationship between intracellular AA deficiency (reported in HIV‐infection) and in vitro cytotoxicity in the presence of SMX metabolites (which has been used as a marker for sulfonamide hypersensitivity). Peripheral blood mononuclear cells (PBMC) were obtained from HIV‐positive patients and healthy controls. PBMC AA concentrations and SMX‐NO reduction were determined by HPLC. PBMC from each subject were also exposed to 0.1‐1.0 mM SMX‐NO for 2 h., followed by overnight incubation in media. Cytotoxicity was quantified using YO‐PRO‐1® fluorescence. In preliminary results from 22 subjects, intracellular AA was strongly correlated with PBMC reduction of SMX‐NO (r=0.73; P=0.0001). In addition, AA was depleted during exposure to SMX‐NO, with a strong linear correlation between nmoles SMX‐NO reduced and nmoles AA depleted (r=0.75; P