Catecholamine potentiation of carbon tetrachloride-induced hepatotoxicity in mice

Abstract

Mice were treated with slightly greater than the organ dysfunction ED50 of carbon tetrachloride (CCl 4) administered in oil intraperitoneally. Simultaneous treatment with epinephrine or norepinephrine in oil administered subcutaneously potentiated the hepatotoxicity induced by CCl 4 treatment. By using 14C- dl-epinephrine and norepinephrine, it was shown that their subcutaneous administration in oil resulted in a sustained, gradual release into the blood. The hepatonecrotic effect of CCl 4, measured by changes in serum glutamic pyruvic transaminase (SGPT) activity, was potentiated by epinephrine and norepinephrine when low doses (0.01 and 0.02 ml/kg) of CCl 4 were used. Potentiation was not always demonstrated with a higher dose (0.04 ml/kg) of CCl 4. Maximal SGPT response occurred 24 hours after treatment. Epinephrine and norepinephrine did not significantly alter the time required for the return of SGPT activity to normal levels. Catecholamine treatment 6 hours before or after CCl 4 treatment still resulted in potentiation of CCl 4-induced elevation in SGPT. The results of histopathologic evaluation of the changes seen in the livers of mice used in the SGPT activity experiments complemented the results of the SGPT activity experiments. Epinephrine and norepinephrine did not potentiate the accumulation of triglycerides in the liver of CCl 4-treated mice. Even at doses of CCl 4 which caused an increased hepatic triglyceride concentration (but less than maximal accumulation), there was no increase seen as a result of simultaneous norepinephrine treatment. In a time-response study, maximal hepatic triglyceride concentration occurred at or before 24 hours after treatment. At a high dose (0.04 ml/kg) of CCl 4, epinephrine did cause a significant increase in triglyceride concentration at 2 and 48 hours after treatment, but neither epinephrine nor norepinephrine changed the maximal triglyceride accumulation or altered the return to normal levels in the liver at this dose of CCl 4. At a lower dose (0.02 mg/kg) of CCl 4, neither epinephrine nor norepinephrine caused a significant increase in liver triglyceride concentration at any time.