Elena J. Ochoa

Dapsone induces oxidative stress and impairs antioxidant defenses in rat liver

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.

Prevention of estradiol 17β-d-glucuronide–induced canalicular transporter internalization by hormonal modulation of cAMP in rat hepatocytes

Glucagon- and salbutamol-derived cAMP prevents estrogen-induced alteration of canalicular transporter localization and function via different pathways. Glucagon-derived protection depends on PKA activation, whereas salbutamol protection is exerted through a pathway that depends on Epac/MEK and microtubules.

Tubular effects of acetaminophen in the isolated perfused rat kidney

AbstractThe effects of different acetaminophen (APAP) concentrations (1,5 or 10 mM) on renal function were investigated in the isolated perfused rat kidney (IPK). APAP was added to the perfusion media as a single dose after a equilibration time and control periods. Changes in fractional excretion of sodium (FENa), water

Fibronectin expression in proximal tubules from ischemic rat kidneys without reperfusion

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Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glycoprotein

, glucose (FEglu) and in glomerular filtration rate (GFR) were measured. The lower concentration used only modified the

Renal Transport of Glycine during Glutathione Replenishment in Rats

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