02699nas a2200421   4500000000100000008004100001260001600042653001200058653001200070653001100082653002800093653001600121653002800137653001600165653002300181653001000204653000900214653002100223653000900244653001700253653002800270100001200298700001300310700001200323700001400335700001400349700001500363700002200378700001500400700001500415700001100430700001400441245008400455300001100539490000700550520170600557022001402263       2008                            d  c2008 Aug 0110aAnimals10aDapsone10aFemale10aGlucuronosyltransferase10aGlutathione10aGlutathione Transferase10aHepatocytes10aLipid Peroxidation10aLiver10aMale10aOxidative Stress10aRats10aRats, Wistar10aReactive Oxygen Species1 aVeggi L1 aPretto L1 aOchoa E1 aCatania V1 aLuquita M1 aTaborda DR1 aSánchez Pozzi EJ1 aIkushiro S1 aColeman MD1 aRoma M1 aMottino A00aDapsone induces oxidative stress and impairs antioxidant defenses in rat liver.  a155-630 v833 a<p>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.</p>  a0024-3205