Cellular toxicity of sulfamethoxazole reactive metabolites--II. Inhibition of natural killer activity in human peripheral blood mononuclear cells.
Based on the identification of intracellular esterase activity as one early target of sulfamethoxazole hydroxylamine (SMX-HA), we wished to determine if the metabolite affected immune functions which involve esterases. The natural killer (NK) activity of human peripheral blood mononuclear cells (PBMC) was assessed with a cell concentration fluorescence technique following exposure to SMX-HA. When K562 target cells were incubated (4 hr/37 degrees) with various ratios of untreated PBMC effector to K562 target cells (E:T), NK activity increased from 17.8 +/- 3.1% (mean +/- SEM; N = 12) at an E:T ratio of 5:1 to 46.2 +/- 2.0% at an E:T ratio of 40:1. Pretreatment of fresh PBMC with 0.1 to 1.0 mM SMX-HA produced a concentration-dependent inhibition of NK activity (E:T ratio 40:1) reaching approximately 80% at 1 mM SMX-HA. Maximum suppression of NK activity was completed within a 60-min pretreatment period with measurable inhibition detected within 30 min. The viability of effector cells was not affected by the metabolite during the pretreatment period. Therefore, the SMX-HA effects could not be directly attributed to decreased viability of the effector cells; they were irreversible and could be prevented by the inclusion of exogenous reduced glutathione (GSH) in a concentration-dependent manner. Given the important roles of NK cells in immune responsiveness and host resistance, our findings of rapid functional inactivation of the cytolytic effector function provide a possible link between idiosyncratic drug toxicity and drug effects directly on components of the immune system.
Leeder
J S
JS
Division of Clinical Pharmacology/Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
Nakhooda
A
A
Spielberg
S P
SP
Dosch
H M
HM
D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004950:Esterases / Q000037:antagonists & inhibitors; D005453:Fluorescence; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008099:Liver / Q000187:drug effects; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000633:toxicity
C059873:sulfamethoxazole hydroxylamine; D004950:Esterases; D005978:Glutathione; D013420:Sulfamethoxazole