Toxicity of sulfonamide-reactive metabolites in HIV-infected, HTLV-infected, and noninfected cells.
It has been suggested that the high rates of adverse reactions to sulfonamides among patients with AIDS may be related to an increased sensitivity to reactive drug metabolites among HIV-infected cells. To study this hypothesis, we investigated the toxicity of the hydroxylamine of sulfamethoxazole in HIV-infected and noninfected MOLT-3 cultured human T-lymphoblasts. Toxicity was assessed by trypan blue dye exclusion. The hydroxylamine of sulfamethoxazole produced concentration-dependent toxicity in HIV-infected cells, with marked toxicity seen when HIV-infected cells were incubated with 400 microM of the hydroxylamine (82 +/- 8%); this was significantly greater than the toxicity seen among noninfected cells (p < 0.01). There was no concentration-dependent toxicity seen among noninfected cells or in cells infected with HTLV-I, suggesting that the concentration-dependent toxicity seen was specifically related to HIV infection. HIV-infected cells had significantly lower glutathione concentration than did noninfected cells (p < 0.05). Incubation with the hydroxylamine of sulfamethoxazole produced a concentration-dependent decline in glutathione content that was similar in infected and non-infected cells. Co-incubation with glutathione or N-acetylcysteine significantly reduced the toxicity of hydroxylamine of sulfamethoxazole in HIV-infected cells (p < 0.05). Our data supports the role of reactive sulfonamide metabolites in the pathogenesis of adverse reactions to sulfonamides among patients with AIDS.
J. P. Robarts Research Institute, Department of Paediatrics, Western Ontario, London, Canada.
M J
MJ
Rieder
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R
Krause
I A
IA
Bird
G A
GA
Dekaban
D000328:Adult; D002478:Cells, Cultured; D006800:Deltaretrovirus Infections / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004342:Drug Hypersensitivity / Q000209:etiology; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008954:Models, Biological; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D018675:Toxicity Tests
C059873:sulfamethoxazole hydroxylamine; D013420:Sulfamethoxazole