Role of cytosolic Glutathione S-transferase in protection against Acetaminophen-induced lipid peroxidation in weanling rats

Medical Journal of The Islamic Republic of Iran

Volume 13 - Number 3

Article Type: ---- Unspecified ----
Abstract:

Resistance of the weanling rat to acetaminophen (APAP)-induced hepatotoxicity is manifested with regard to a surge in APAP-glutathione (GSH) conjugate formation in the liver [Allameh et al. Mech Aging Dev 95 (1997) 71]. The present study was conducted to assess the role of this detoxification pathway in APAP-induced lipid peroxidation in liver. Lipid peroxidation measured as thiobarbituric acid reactive substances (TBARS) in rat liver homogenate was observed to be increased due to a decrease in hepatic cellular GSH concentration. Cellular GSH content was relatively lower in growing liver and further decreased in rats treated with either GSH-depleting agents or APAP, whereas adult animals under APAP treatment suffered significantly less depletion of GSH. APAP injection to weanling rats pre-treated with diethylmaleate (DEM) aggravated lipid peroxidation. Administration of a single large dose of APAP (500 mg/kg b.w.) to weanling rats, 3h before sacrifice, which caused 46% GSH depletion, resulted in a 25% increase in lipid peroxidation. Pre-treatment of growing rats with DEM, 30 min before APAP, caused about 70% depletion in GSH content as a result of which there was a further increase (Approx. 1.6 fold) in lipid peroxide formation (control: 37.40; experimental: 60.76 nmol malondialdehyde formation/g tissue). GSH S-transferase activity is not necessarily a determinant of APAP toxicity in adult animals. Unlike adults, in growing tissues the enzyme activity is induced (~40%) in response to a single overdose of APAP. When these data are discussed in relation to our earlier study, it could be concluded that APAP-dependent induction of GSH S-transferases is responsible for increased APAP-GSH conjugate formation, which facilitates inactivation of NAPQI as well as other toxic metabolites of lipid peroxidation.