title: Combined ascorbate and glutathione deficiency leads to decreased cytochrome b5 expression and impaired reduction of sulfamethoxazole hydroxylamine.
abstract: Sulfonamide antimicrobials such as sulfamethoxazole (SMX) have been associated with drug hypersensitivity reactions, particularly in patients with AIDS. A reactive oxidative metabolite, sulfamethoxazole-nitroso (SMX-NO), forms drug-tissue adducts that elicit a T-cell response. Antioxidants such as ascorbic acid (AA) and glutathione (GSH) reduce SMX-NO to the less reactive hydroxylamine metabolite (SMX-HA), which is further reduced to the non-immunogenic parent compound by cytochrome b (5) (b5) and its reductase (b5R). We hypothesized that deficiencies in AA and GSH would enhance drug-tissue adduct formation and immunogenicity toward SMX-NO and that these antioxidant deficiencies might also impair the activity of the b5/b5R pathway. We tested these hypotheses in guinea pigs fed either a normal or AA-restricted diet, followed by buthionine sulfoximine treatment (250 mg/kg SC daily, or vehicle); and SMX-NO (1 mg/kg IP 4 days per week, or vehicle), for 2 weeks. Guinea pigs did not show any biochemical or histopathologic evidence of SMX-NO-related toxicity. Combined AA and GSH deficiency in this model did not significantly increase tissue-drug adduct formation, or splenocyte proliferation in response to SMX-NO. However, combined antioxidant deficiency was associated with decreased mRNA and protein expression of cytochrome b (5), as well as significant decreases in SMX-HA reduction in SMX-NO-treated pigs. These results suggest that SMX-HA detoxification may be down-regulated in combined AA and GSH deficiency. This mechanism could contribute to the higher risk of SMX hypersensitivity in patients with AIDS with antioxidant depletion.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-1102, USA.
authors.forename: Sachin
authors.initials: S
authors.lastname: Bhusari
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Abouraya
authors.forename: Marcia L
authors.initials: ML
authors.lastname: Padilla
authors.forename: Marie E
authors.initials: ME
authors.lastname: Pinkerton
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Drescher
authors.forename: James C
authors.initials: JC
authors.lastname: Sacco
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Trepanier
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism*; D001206:Ascorbic Acid Deficiency / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D042966:Cytochrome-B(5) Reductase / Q000235:genetics / Q000378:metabolism; D015786:Cytochromes b5 / Q000235:genetics / Q000378:metabolism*; D004342:Drug Hypersensitivity / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D006168:Guinea Pigs; D008658:Inactivation, Metabolic; D008099:Liver / Q000378:metabolism; D008297:Male; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000890:Anti-Infective Agents; D000975:Antioxidants; C059873:sulfamethoxazole hydroxylamine; D015786:Cytochromes b5; D042966:Cytochrome-B(5) Reductase; D005978:Glutathione; D013420:Sulfamethoxazole; D001205:Ascorbic Acid