Repeated acetaminophen dosing in rats: adaptation of hepatic antioxidant system

Abstract

<jats:p> Repeated dosing of acetaminophen (paracetamol) to rats is reported to decrease their sensitivity to its hepatotoxic effects, which are associated with oxidative stress and glutathione depletion. </jats:p><jats:p> We determined if repeated acetaminophen dosing produced adaptive response of key antioxidant system enzymes. </jats:p><jats:p> Male rats (Sprague-Dawley, 10 weeks) were given 800, 1200, or 1600 mg/kg/day acetaminophen by oral gavage for 4 days. Liver was assayed for oxidative stress and antioxidant markers: malondialdehyde (MDA), thiobar-bituric acid reactive substance (TBARS), total antioxidant status (TAS), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD), catalase (CAT), and superoxide dismutase (SOD), and alanine transaminase (ALT) as a marker of hepatocellular injury. </jats:p><jats:p> Acetaminophen at 1200/1600 mg/kg decreased GSH 26/47%, GPx 21/26%, CAT 35/28%, SOD 21/12%; and TAS 28/18% (correlated with CAT, r=0.91; SOD, r=0.66; GPx, r = 0.45). Despite antioxidant deficiencies, and no TBARS change, MDA decreased 26%/33%/37% at 800/1200/1600 mg/kg, which correlated with increased GR (61%/62%/76%, r = 0.77) and G6PD (130%/110%/190%, r = 0.78). </jats:p><jats:p> Both MDA (r = 0.68) and G6PD (r = 0.71) correlated with hepatic ALT, which decreased 27%o/43%/48%, respectively. </jats:p><jats:p> Resistance to acetaminophen hepatotoxicity produced by repeated exposure is partially attributable to upregulation of hepatic G6PD and GR activity as an adaptive and protective response to oxidative stress and glutathione depletion. </jats:p>

Effects of some analgesic anaesthetic drugs on human erythrocyte glutathione reductase: anin vitrostudy

“…Similar results were obtained in previous studies [15 -18]. Similar results were obtained in different study in hepatic rat GR for acetaminophen (paracetamol) [27].…”

Supplementation of Psidium guajava (Guava) Fruit Polysaccharide Attenuates Paracetamol-induced Liver Injury by Enhancing the Endogenous Antioxidant Activity

“…Body weight reduction is one of the presenting features in drug-induced liver injury (O'Brien et al 2000) and the significant body weight reduction was found following the PCM induction in the present study. The body weight reduction might be owing to impaired liver function as one of its functions is to breakdown the nutrients and release into the blood stream.…”

Hepatoprotective Effects of the Water Extract from Adzuki Bean Hulls on Acetaminophen-Induced Damage in Rat Liver

“…Furthermore, it is highly possible that adzuki extract may eliminate reactive intermediates, since Cardador-Martinez et al (18) have reported that bean hulls exert antioxidative properties, as represented by their capacity to either scavenge free radicals or inhibit lipid peroxidation. The decreases in activities of catalase and GSH peroxidase in AAP-administrated groups suggest the increased lipid peroxide content (19). The hepatic catalase and GSH peroxidase activities in the AAP-treated group were decreased by 23.5% and 11.2%, respectively (Table 3).…”