EVALUATION OF HEPATIC TOXICITY OF SEVEN-DAY REPEATED-DOSE GLUTATHIONE-DEPLETING REGIMENS IN RATS

Abstract

Glutathione (GSH) depletion is a common method for examining the role of oxidative stress in the toxicity of novel compounds. Several treatment regimens for inducing hepatic GSH depletion in rats were examined for their suitability for use in a 7-day repeated-dose paradigm. Male Wistar rats (5/treatment) were administered either 2,6-dimethyl-2,5-heptadien-4-one (phorone, 250 mg/kg ip), diethylmaleate (DEM, 600 mg/kg ip), ethanol in drinking water (150 mL/L), or L-buthionine-SR-sulfoximine (BSO) in drinking water (4.446 g/L) with and without supplemental ip administration (890 mg/kg bid) for 7 days. Additional groups of 5 animals were given phorone or DEM and sacrificed 2 h after dose. Significant body weight gain suppression relative to control was evident in all treated groups but only animals given the ip/water BSO treatment resulted in mean weight loss (4%). Liver weights were significantly increased by 7 days of phorone treatment and decreased by ip/water BSO treatment. No clinically significant effects were noted on hepatic serum chemistry parameters. No hepatic histopathology was produced by any treatment, but phorone produced increased hepatocellular mitoses. BSO administered in the drinking water without supplemental ip administration appeared to be the most suitable model for routine assessment of hepatic GSH depletion in mechanistic models. The model was practical, did not induce hepatic pathology, and produced marked decreases in hepatic cytosolic GSH and moderate decreases in hepatic mitochondrial GSH.

Keywords: :

• Diethylmaleate Ethanol Glutathione Depletion L-buthionine Sr -sulfoximine Liver Phorone Rat