Blood ammonia levels and hepatic encephalopathy induced by CCl4 in rats.
An investigation of the mechanism of development of hepatic encephalopathy induced by CCl4 was performed in rats. CCl4 (1.0 ml/kg three times per week for over 10 weeks) caused hepatic encephalopathy in 80% of the treated rats. Accompanying the hepatic encephalopathy were hematemesis, abdominal dropsy, and hyperammonemia, conditions observed in hepatic coma patients. The blood ammonia levels were tremendously increased in only those rats with hepatic encephalopathy. Hepatic activities of carbamylphosphate synthetase (CPS) and argininosuccinate synthetase (ASS), important enzymes of the urea cycle, were significantly inhibited by CCl4. However, the causality between the inhibition of CPS or ASS activity and the increase in blood ammonia levels was not observed. On the other hand, the content of ATP, which is a substrate of CPS and ASS, was decreased by 60% in liver of rats with hepatic encephalopathy. The activity of Mg2+-ATPase which can decompose hepatic ATP was increased by 60 and 300% in mitochondria and microsomes, respectively, of livers of rats with CCl4-induced encephalopathy. There was a good correlation between the decreased hepatic ATP content and the increased mitochondrial Mg2+-ATPase activity. Furthermore, there was also a good correlation between the increase in blood ammonia levels and the increase in Mg2+-ATPase activity in microsomes. These findings suggest that hyperammonemia, which was produced by the decrease in hepatic content and by the inhibition of CPS and ASS, may play an important role in induction of hepatic encephalopathy.
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000502:physiology; D000641:Ammonia / Q000097:blood*; D000818:Animals; D001124:Argininosuccinate Synthase / Q000378:metabolism; D017301:Ca(2+) Mg(2+)-ATPase / Q000096:biosynthesis; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000037:antagonists & inhibitors; D002251:Carbon Tetrachloride / Q000633:toxicity*; D006501:Hepatic Encephalopathy / Q000097:blood / Q000139:chemically induced*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000641:Ammonia; D000255:Adenosine Triphosphate; D002251:Carbon Tetrachloride; D017301:Ca(2+) Mg(2+)-ATPase; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D001124:Argininosuccinate Synthase