title: Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver.
abstract: Dapsone (DDS) is currently used in the treatment of leprosy, malaria and in infections with Pneumocystis jirovecii and Toxoplasma gondii in AIDS patients. Adverse effects of DDS involve methemoglobinemia and hemolysis and, to a lower extent, liver damage, though the mechanism is poorly characterized. We evaluated the effect of DDS administration to male and female rats (30 mg/kg body wt, twice a day, for 4 days) on liver oxidative stress through assessment of biliary output and liver content of reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and expression/activities of the main antioxidant enzymes glutathione peroxidase, superoxide dismutase, catalase and glutathione S-transferase. The influence of DDS treatment on expression/activity of the main DDS phase-II-metabolizing system, UDP-glucuronosyltransferase (UGT), was additionally evaluated. The involvement of dapsone hydroxylamine (DDS-NHOH) generation in these processes was estimated by comparing the data in male and female rats since N-hydroxylation of DDS mainly occurs in males. Our studies revealed an increase in the GSSG/GSH biliary output ratio, a sensitive indicator of oxidative stress, and in lipid peroxidation, in male but not in female rats treated with DDS. The activity of all antioxidant enzymes was significantly impaired by DDS treatment also in male rats, whereas UGT activity was not affected in any sex. Taken together, the evidence indicates that DDS induces oxidative stress in rat liver and that N-hydroxylation of DDS was the likely mediator. Impairment in the activity of enzymatic antioxidant systems, also associated with DDS-NHOH formation, constituted a key aggravating factor.
authors.affiliation: Facultad de Ciencias Bioquímicas y Farmacéuticas, Instituto de Fisiología Experimental, U.N.R.-CONICET, Rosario, Argentina.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Veggi
authors.forename: Luciana
authors.initials: L
authors.lastname: Pretto
authors.forename: Elena J
authors.initials: EJ
authors.lastname: Ochoa
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Catania
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Luquita
authors.forename: Diego R
authors.initials: DR
authors.lastname: Taborda
authors.forename: Enrique J
authors.initials: EJ
authors.lastname: Sánchez Pozzi
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ikushiro
authors.forename: Michael D
authors.initials: MD
authors.lastname: Coleman
authors.forename: Marcelo G
authors.initials: MG
authors.lastname: Roma
authors.forename: Aldo D
authors.initials: AD
authors.lastname: Mottino
mesh_terms: D000818:Animals; D003622:Dapsone / Q000494:pharmacology*; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D003622:Dapsone; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D005978:Glutathione