title: Plasma ascorbate deficiency is associated with impaired reduction of sulfamethoxazole-nitroso in HIV infection.
abstract: OBJECTIVE
  The objective of these studies was to determine the role of ascorbate deficiency in HIV infection in the defective detoxification of sulfamethoxazole-nitroso, the metabolite thought to mediate sulfonamide hypersensitivity reactions.
  
  
  METHODS
  Fifty-one HIV-infected patients and 26 healthy volunteers were evaluated. Vitamin supplementation histories were obtained, and blood samples were collected for determination of plasma ascorbate, dehydroascorbate, and cysteine concentrations, erythrocyte glutathione concentrations, and plasma reduction of sulfamethoxazole-nitroso in vitro.
  
  
  RESULTS
  Plasma ascorbate concentrations were significantly lower in HIV-positive patients not taking vitamin supplements (29.5 +/- 22.3 microM) than in healthy subjects (54.8 +/- 22.3 microM; P = 0.0005) and patients taking 500-1000 mg of ascorbate daily (82.5 +/- 26.3 microM; P < 0.0001). Plasma ascorbate deficiency was strongly correlated with impaired reduction of sulfamethoxazole-nitroso to its hydroxylamine (r = 0.60, P < 0.0001), and during in vitro reduction, the loss of plasma ascorbate was strongly associated with the amount of nitroso reduced (r = 0.70, P < 0.0001). Ascorbate added ex vivo normalized this reduction pathway. Erythrocyte glutathione concentrations were significantly lower in HIV-positive patients (0.98+/-0.32 mM) than in healthy subjects (1.45+/-0.49 mM; P = 0.001), but this finding was unrelated to ascorbate supplementation. There was trend toward lower plasma cysteine concentrations in patients (8.4+/-3.9 microM) than in controls (10.3+/-4.3 microM), but this trend was similarly unrelated to ascorbate supplementation. Dehydroascorbate concentrations were not significantly higher in HIV-positive patients (7.4+/-10.5%) than in healthy controls (4.0+/-6.2%), even in the subset of patients taking ascorbate (8.4+/-9.4%).
  
  
  CONCLUSIONS
  Ascorbate deficiency is common in HIV-positive patients and is associated with impaired detoxification of sulfamethoxazole-nitroso, the suspected proximate toxin in sulfonamide hypersensitivity. Patients taking daily ascorbate supplements (500-1000 mg) achieved high plasma ascorbate concentrations and did not show this detoxification defect. Ascorbate deficiency (or supplementation) was not associated with changes in glutathione or cysteine concentrations. These data suggest that ascorbate deficiency, independent of thiol status, may be an important determinant of impaired drug detoxification in HIV infection.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin--Madison, Madison, WI 53706-1102, USA. LATrepanier@svm.vetmed.wisc.edu
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Trepanier
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Yoder
authors.forename: Sunil
authors.initials: S
authors.lastname: Bajad
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Beckwith
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bellehumeur
authors.forename: Frank M
authors.initials: FM
authors.lastname: Graziano
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000378:metabolism; D001205:Ascorbic Acid / Q000097:blood; D001206:Ascorbic Acid Deficiency / Q000150:complications* / Q000378:metabolism*; D016516:CD4-CD8 Ratio; D016022:Case-Control Studies; D003545:Cysteine / Q000097:blood; D003683:Dehydroascorbic Acid / Q000097:blood; D005260:Female; D005978:Glutathione / Q000097:blood; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D013420:Sulfamethoxazole / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; C059873:sulfamethoxazole hydroxylamine; D005978:Glutathione; D013420:Sulfamethoxazole; D003545:Cysteine; D001205:Ascorbic Acid; D003683:Dehydroascorbic Acid