INVESTIGADORES
SANCHEZ POZZI Enrique Juan
artículos
Título:
Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver
Autor/es:
VEGGI, LUIS M; PRETTO, LUCIANA; OCHOA, J ELENA; CATANIA, VIVIANA A; LUQUITA, MARCELO G; TABORDA, DIEGO R; SANCHEZ POZZI, EJ; IKUSHIRO, S; COLEMAN, MICHAEL D; ROMA, MARCELO G; MOTTINO, ALDO D
Revista:
LIFE SCIENCES
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Año: 2008 vol. 83 p. 155 - 163
ISSN:
0024-3205
Resumen:
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.