COMPARATIVE EFFECTS OF ACETAMINOPHEN ON GLUTATHIONE HOMEOSTASIS AND KEY SULPHYDRYL PROTEINS IN RATS AND MICE.

Abstract

Acetaminophen toxicity has been integrally related to disturbed glutathione homeostasis in vivo. This alteration in the glutathione dynamics has been associated with production of N-acetyl p-benzoquinone imine (NAPQI). However, there is a dearth of information describing the possible effect of acetaminophen on glutathione homeostasis either in vitro or in vivo. The present study evaluated the effect of glutathione on the potentials of acetaminophen to modulate free radical induced hepatic and cerebral lipid damage consequent from several pro-oxidant-induced redox imbalances under in vitro and in vivo conditions. Besides, the effects of acetaminophen on the activities of some sulphydryl proteins as well as enzyme-dependent purinergic signaling were also evaluated under in vitro and in vivo conditions. The results showed that glutathione positively enhanced the antioxidant potentials of acetaminophen especially in its in vitro ability to scavenge free radicals, reduce Fe3+, chelate Fe2+ and inhibits oxidant-induced damage of both hepatic and cerebral lipids. Conversely, acetaminophen has no inhibitory effect on the activities of sulphydryl proteins; cerebral sodium pump and hepatic δ-aminolevulinic acid dehydratase as well as purinergic enzymes; 5’-nucleotidase and Nucleoside Triphospate Diphosphohydrolase. However, acetaminophen evoked an increased lipid peroxidation in vivo and this effect was associated with increased ability of the hepatic and cerebral tissues to oxidize thiols. In addition, while there was a concomitant decrease in the activities of the sulphydryl proteins, there was an increase in the activities of the purine hydrolyzing enzymes evaluated. In conclusion, the present study demonstrated that the molecular events associated with altered glutathione homeostasis in cases of acetaminophen overdose is multifactorial and may initially involve the direct participation of acetaminophen wherein the tripepetide enhanced its antioxidant properties. At inhibits oxidant-induced damage of both hepatic and cerebral lipids. Conversely, acetaminophen has no inhibitory effect on the activities of sulphydryl proteins; cerebral sodium pump and hepatic δ-aminolevulinic acid dehydratase as well as purinergic enzymes; 5’-nucleotidase and Nucleoside Triphospate Diphosphohydrolase. However, acetaminophen evoked an increased lipid peroxidation in vivo and this effect was associated with increased ability of the hepatic and cerebral tissues to oxidize thiols. In addition, while there was a concomitant decrease in the activities of the sulphydryl proteins, there was an increase in the activities of the purine hydrolyzing enzymes evaluated. In conclusion, the present study demonstrated that the molecular events associated with altered glutathione homeostasis in cases of acetaminophen overdose is multifactorial and may initially involve the direct participation of acetaminophen wherein the tripepetide enhanced its antioxidant properties. At exacerbate a further depletion of the antioxidant tripeptide. Apparently, the toxicity of acetaminophen may also involve disturbed signaling processes involving the purinergic messengers.