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Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8⁺ cells by the hydroxylamine of sulfamethoxazole

DAVID A. HESS^*, MARGARET E. SISSON, HAMZA SURIA, JOHN WIJSMAN, RAM PUVANESASINGHAM, JOAQUÍN MADRENAS and MICHAEL J. RIEDER^§1,2

^* Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada;
Departments of Medicine, Microbiology and Immunology, University of Western Ontario, Transplantation and Immunobiology Group, John P. Robarts Research Institute, London, Ontario, Canada; and
^§ Departments of Pediatrics, Pharmacology and Toxicology, Children's Hospital of Western Ontario, University of Western Ontario, Gene Therapy and Molecular Virology Group, John P. Robarts Research Institute, London, Ontario, Canada

¹Correspondence: Departments of Pediatrics and Pharmacology and Toxicology, Children's Hospital of Western Ontario, University of Western Ontario, 800 Commissioners Rd. E. London, Ontario, Canada, N6J 1Y5. E-mail: mrieder{at}julian.uwo.ca

Treatment with sulfonamide antibiotics in HIV-infected patients is associated with a high incidence (> 40%) of adverse drug events, including severe hypersensitivity reactions. Sulfonamide reactive metabolites have been implicated in the pathogenesis of these adverse reactions. Sulfamethoxazole hydroxylamine (SMX-HA) induces lymphocyte toxicity and suppression of proliferation in vitro; the mechanism(s) of these immunomodulatory effects remain unknown. We investigated the cytotoxicity of SMX-HA via apoptosis on human peripheral blood mononuclear cells and purified cell subpopulations in vitro. CD19⁺, CD4⁺, and CD8⁺ cells were isolated from human peripheral blood by positive selection of cell surface molecules by magnetic bead separation. SMX-HA induced significant CD8⁺ cell death (67 ± 7%) at 100 µM SMX-HA, with only minimal CD4⁺ cell death (8 ± 4%). No significant subpopulation toxicity was shown when incubated with parent drug (SMX). Flow cytometry measuring phosphatidylserine externalization 24 h after treatment with 100 µM and 400 µM SMX-HA revealed 14.1 ± 0.7% and 25.6 ± 4.2% annexin-positive cells, respectively, compared to 3.7 ± 1.2% in control PBMCs treated with 400 µM SMX. Internucleosomal DNA fragmentation was observed in quiescent and stimulated PBMCs 48 h after incubation with SMX-HA. Our data show that CD8⁺ cells are highly susceptible to the toxic effects of SMX-HA through enhanced cell death by apoptosis.—Hess, D. A., Sisson, M. E., Suria, H., Wijsman, J., Puvanesasingham, R., Madrenas, J., Rieder, M. J. Cytotoxicity of sulfonamide reactive metabolites: apoptosis and selective toxicity of CD8⁺ cells by the hydroxylamine of sulfamethoxazole.

Key Words: cytochrome P450 • MACS • apoptosis • cell viability

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