Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides

Abstract

Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apoptosis and necroptosis. ROS can also serve as "danger signals," priming immune cells to mount an immunological reaction. We recruited 26 sulfa-hypersensitive (HS) patients, 19 healthy control subjects, and 6 sulfa-tolerant patients to this study. Peripheral blood monocytes and platelets were isolated from blood samples and analyzed for in vitro cytotoxicity,ROS and carbonyl protein formation,lipid peroxidation, and GSH (glutathione) content after challenge with SMX-HA.When challenged with SMX-HA,cells isolated from sulfa-HS patients exhibited significantly (P ࣘ .05) higher cell death, ROS and carbonyl protein formation, and lipid peroxidation. In addition, there was a high correlation between cell death in PBMCs and ROS levels. There was also depletion of GSH and lower GSH/GSSG ratios in peripheral blood mononuclear cells from sulfa-HS patients. The amount of ROS formed was negatively correlated with intracellular GSH content. The data demonstrate a major role for oxidative stress in in vitro cytotoxicity of SMX reactive metabolites and indicate increased vulnerability of cells from sulfa-HS patients to the in vitro challenge. Keywordsidiosyncratic drug reactions, in vitro diagnosis, drug allergy, adverse drug reactions, sulfamethoxazole, sulfamethoxazole hydroxylamine

Variability of the Genes Involved in the Cellular Redox Status and Their Implication in Drug Hypersensitivity Reactions

“…In addition, the in vitro analysis of monocytes and platelets from sulfamethoxazole hypersensitivity patients challenged with sulfamethoxazole metabolites demonstrated an increased vulnerability of these cells. These pieces of evidence show a major role for oxidative stress in cytotoxicity of sulfamethoxazole and suggest a role of the redox status in the development of specific immunological drug reactions [16].…”

“…Thus, injured cells might release alarm signals, such as reactive oxygen intermediates that might be capable of modifying the immune response. In this regard, the oxidative stress status may contribute as a key factor in the development of DHRs [16,22]. Genetic association studies have documented several findings supporting this hypothesis [23,24].…”

“…Elzagallaai et al have characterized the cytotoxicity, ROS generation, carbonyl protein formation, lipid peroxidation, and GSH content in monocytes and platelets from patients with specific immune hypersensitivity to sulfonamides [16]. The sulfamethoxazole N-hydroxylamine reactive metabolite, generated through cytochrome P450 oxidation of the parental drug, can oxidize reactive cysteine thiols generating reactive oxygen species that cause cytotoxicity.…”

“…Furthermore, several factors may contribute to the occurrence of DHRs. In this regard, it has been pointed out that the reactive metabolites generated by the bioactivation of a particular drug and its binding to cellular macromolecules might be related to DHR development [16,17]. Thus, -lactam antibiotics form adducts with high molecular weight proteins through a covalent bond generating a hapten-carrier formation for immune activation [18].…”

Drug and Chemical Allergy: A Role for a Specific Naive T-Cell Repertoire?

“…Our immune system must be able to discriminate harmless non-self from dangerous non-self. There is multiple evidence that some chemicals have found very specific ways to activate the immune system by acting as danger signals (55,64,68,(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102). Therefore, our immune system may have evolved to mount a specific defense mechanism avoiding prolonged exposure to reactive drugs/chemicals.…”