ROLE OF CYTOSOLIC GL U TATHIONE S- T RANSFERASES IN PRO TEC TION AGAINS T ACE TAMINOPHEN-INDUCED LIPID PEROXIDATION IN WEANLING RATS

Resistance of the weanling rat to acetaminophen (AP AP)-induced hepatotoxicity is manifested with regard to a surge in APAP-glutathione (OSH) 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 APAPinduced lipid per6xidationin the 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. AP AP 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, 3 h 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 indu.ced single overdose of APAP. When these data are discussed in relation to our earlier study, it could be concluded that APAP-dependent induction of GSHS-transferases is responsible for increased APAP-GSH conjugate formation which facilitates inactivation of NAPQI as well as other toxic metabolites of lipid peroxidation.