INDUCTION OF AN ATPASE INHIBITOR PROTEIN BY PROPYLTHIOURACIL AND PROTECTION AGAINST PARACETAMOL (ACETAMINOPHEN) HEPATOTOXICITY IN THE RAT

1 The purpose of the present study was to test the following hypothesi s: propylthiouracil (PTU) treatments of rats induces an increase in th e concentration and activity of the mitochondrial ATPase (m-ATPase) in hibitor protein (IF1). The PTU-induced elevated baseline levels of thi s inhibitor protein inactivated m-ATPase, and prevented hepatotoxicity by a toxic dose of acetaminophen (AAP) (paracetamol), by maintaining hepatic adenosine 5'-triphosphate (ATP) levels. 2 Male Wistar rats wer e either gavaged with a toxic dose of AAP alone, or after pretreatment with PTU for periods of 3 and 12 days. 3 Twenty four hours after acet aminophen treatment alone? toxicity was manifested by: an approximatel y 10 fold increase in serum transaminase levels (serum glutamic oxaloa cetic transaminase and serum glutamic pyruvic transaminase); depletion of hepatic reduced glutathione (GSH) and ATP levels; loss of inhibito r protein activity, and extensive pericentral necrosis of the hepatocy tes. Propylthiouracil pretreatment for 12 days enhanced the concentrat ion of the following metabolites in the liver: ATP (1.5 fold), ATPase inhibitor protein (IF1) (4.5 fold), and reduced glutathione (1.3 fold) , while the activity of the inhibitor protein increased 2 fold. When t he PTU treated rats were challenged with FLAP, transaminases were not elevated, and only sporadic areas of necrosis were detected by histolo gical examination of the liver tissue. In contrast to the 12 day treat ment with PTU the 3 day treatment had no protection against AAP. No hi stological evidence of protection was manifested and the transaminases were not different from AAP treated controls. Most of the protective metabolites were depleted. 4 Our findings suggest that PTU-induced inc reased concentration of inhibitor protein and GSH, are contributing fa ctors in the prevention of hepatotoxicity by maintaining hepatic m-ATP levels and reducing the harmful effect of the toxic metabolite of FLA P.