Glutathione Alterations in Rat Liver After Acute and Subacute Oral Administration of Paracetamol

Abstract

1. The effect on hepatic glutathione was studied in rats pretreated orally with various dosages of paracetamol (acetaminophen) for varying time intervals. 2. Paracetamol caused a dose-dependent depletion of hepatic glutathione, the maximum depletion occurring 3 h after acute dosing, the levels returning to normal by 12 h after low doses (0-1 or 0-25 g/kg, p.o.) and by 72 h after the highest doses (1 g/kg, p.o.). 3. Before returning to normal, the liver glutathione levels became significantly greater than the control values (35-40%) at 24 and 48 h in 0-5 and 1 g/kg paracetamol-treated rats, respectively, suggesting thereby a 'glutathione rebound action' of paracetamol-pretreatment. 4. In contrast with the acutely treated rats, the liver glutathione content remained unchanged when 0-5 g/kg paracetamol was administered twice daily for 7 consecutive days. 5. Fasting caused a significant reduction in hepatic glutathione, the glutathione stores were replenished within 6 h after feeding. 6. The results suggest that the hepatic glutathione levels are reversibly depleted by single large doses of paracetamol, while the glutathione depletory effect appears to decrease after the repeated administration of this hepatotoxic agent.

Effect of Haemorrhage on Hepatic Glutathione Concentration: An Experimental Study in the Pig

“…On the other hand it was demonstrated in the present study that there was a rebound elevation of the hepatic GSH level 24 h after blood loss. The rebound elevation of GSH has also been shown in previous animal experiments in which the animals were given non-toxic doses of paracetamol (Buttar, Chow and Downie 1977) Since the enzyme in the last step of the 7-glutamyI cycle, glutathione synthetase, is under the feedback inhibition of GSH (Tate and Meister, 1974), the rglutamyl cycle ensures the repletion of hepatic GSH upon the withdrawal of the factors which niay deplete GSH and in the presence of an adequate supply of amino HCIGS 3nCl Ai IT. The reduction in hepatic GSH level at 6 h following haemorrhage in this ammal model was about 30% of the pre-bleed value.…”

Elevated Mitochondrial Cytochrome P450 2E1 and Glutathione S-Transferase A4-4 in Streptozotocin-Induced Diabetic Rats

“…Enzyme assay and measurement of oxidative stress. GSH levels were determined as protein-free sulfhdryl content using Ellman's reagent (25) or by the method of Tietze (26). Lipid peroxidation was estimated by measuring thiobarbituric acid-reactive substances (TBARS), using MDA as a standard (27).…”

Enhancement of acetaminophen-induced chronic hepatotoxicity in restricted fed rats: a nonclinical approach to acetaminophen-induced chronic hepatotoxicity in susceptible patients

“…Laboratory rodents differ from humans in many ways, including smaller genetic heterogeneity and narrower variation in diet and lifestyle. Further, intact rats more easily adapt to drugs including APAP than humans (O'Brien et al, 2000;Buttar et al, 1976Buttar et al, , 1977Strubelt et al, 1979;Poulsen and Thomsen, 1988;Shayiq et al, 1999). Thus, we employed daytime restricted fed (RF) rats as a modified-nutritional state model for human responders to APAP-induced hepatotoxicity because daytime-RF rats are well known to show some characteristic adaptive changes in energy metabolism, glucose synthesis and fatty acid oxidation associated with a shift of the animal's circadian rhythms (Baez-Ruiz et al, 2005;Leveille and Chakrabarty, 1968;Satoh et al, 2006;Wu et al, 2008) and to show acceleration of hepatic gluconeogenesis under restricted feeding conditions (Kobayashi et al, 2011) .…”