Differential inhibitory effects of carbon tetrachloride on the hepatic plasma membrane, mitochondrial and endoplasmic reticular calcium transport systems: implications to hepatotoxicity

Mitochondrial, endoplasmic reticular and plasma membrane fractions were isolated by a new method from control male Fischer 344 rats and rats given CCl 4 by gavage. After 1 h of CCl 4 treatment, rats were in glucose and pancreatic hormone balance but plasma levels of T 3 and T 4 were decreased 29 and 22%, respectively. After 24 hours of CCl 4 treatment, rats were: hypoglycaemic and insulin and glucagon levels were increased 33‐ and 35‐fold, respectively; total T 4 levels were decreased 62%; while total T 3 levels were normalized. In liver fractions from CCI 4 ‐treated rats, 1 h after CCl 4 administration: (i) calcium binding was decreased 65% in the mitochondrial fraction, 66% in the endoplasmic reticular fraction and 46% in the plasma membrane fraction; (ii) calcium uptake was decreased 59% in the mitochondrial fraction, 46% in the endoplasmic reticular fraction and 37% in the plasma membrane fraction. After 24 h of CCl 4 administration: (i) calcium binding was decreased 57% in the mitochondrial fraction, 50% in the endoplasmic reticular fraction and 71% in the plasma membrane fraction; (ii). calcium uptake was decreased 55% in the mitochondrial fraction, 17% in the endoplasmic reticular fraction and 53% in the plasma membrane fraction. In vitro studies indicated the plasma membrane calcium transport system to be rapidly (within a minute) and strongly (>90%) inhibited by CCl 4 . We conclude that CCl 4 produces a differential inhibitory effect on the hepatoctye calcium pumps that are implicated with hepatocellular damage. Copyright © 2001 John Wiley & Sons, Ltd.