Hepatic ATP content and hyperammonemia induced by CCl 4 in rats

Abstract

An investigation of the mechanism of development of hyperammonemia observed in CCl 4-induced hepatic encephalopathy was performed in rats. CCl 4 (1.0 ml/kg 3 times per week for over 10 weeks) caused a severe hyperammonemia and depletion of hepatic ATP contents in only those rats with hepatic encephalopathy. However, CCl 4 (1.0 ml/kg 3 times per week for 7 weeks) did not cause hepatic encephalopathy and did not change in blood ammonia levels. Administration of 2,4-dinitrophenol (2,4-DNP) in these CCl 4-treated rats caused hepatic encephalopathy within 30 min after injection and then the increase of 140 μg/dl in blood ammonia levels and the decrease of 80% in hepatic ATP contents were observed. However, the administration of 2,4-DNP in CCl 4-untreated rats did not cause hepatic encephalopathy within 30 min after injection although the increase of 70 μg/dl in blood ammonia levels and the decrease of 80% in hepatic ATP contents were observed. Hepatic activities of carbamylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), important enzymes of the urea cycle, were significantly inhibited by 85% and 60% respectively, in rats treated with CCl 4 plus 2,4-DNP. However, in rats treated with 2,4-DNP and without CCl 4, the hepatic activities of CPS and ASS were inhibited only 25% and 0%, respectively. These findings suggest that the severe hyperammonemia, which may be produced by the decrease of hepatic ATP content and the inhibition of CPS and ASS, may play an important role in induction of hepatic encephalopathy.