Increased reactive oxygen stress in cells of patients with drug hypersensitivity

Abstract

Background Adverse drug reactions are important problems associated with therapy. The mechanisms of drug hypersensitivity remain largely unknown. We have previously identified altered response to reactive drug metabolites as an important component of drug hypersensitivity. Methods Peripheral blood mononuclear cells from patients with a history of sulfonamide hypersensitivity (n=6) and normal controls (n=6) were incubated with increasing concentrations of sulfamethoxazole and sulfamethoxazole hydroxylamine and the degree of reactive oxygen stress (ROS) determined using DH2TH after a 24 hour incubation. Cell viability was determined using an MTT method and the degree of apoptosis determined using FACS. Results A concentration-dependent increase in the amount of ROS was seen in the cells of both controls and patients, with significantly more ROS (p>0.05) seen in the cells of patients than controls. This was associated with a significant increase in cell death in the cells of patients (p>0.01) versus controls. The cells of controls showed significantly more apoptosis than did the cells of controls (p>0.05), with the cells of patients showing significantly more necrosis (p>0.05). No increases in ROS or cell death were seen in the presence of the parent drug. Conclusions The cells of patients who had reactions had significantly more ROS and necrosis than control cells, suggesting that altered response to ROS may be a critical factor in drug hypersensitivity. Clinical Pharmacology & Therapeutics (2004) 75, P26–P26; doi: 10.1016/j.clpt.2003.11.096