Studies on the mechanism of the protective action of 16,16-dimethylPGE2 in carbon tetrachloride induced acute hepatic injury in the rat

We have previously demonstrated the partial protection of the rat liver by 16,16-dmPGE2 (DMPG) against a number of hepatotoxins including carbon tetrachloride (CCl4). However, it has not been determined whether hepatoprotection by DMPG represents a true "cytoprotective" action or if merely accomplished through inhibition of CCl4 metabolism to reactive, toxic trichoromethyl (CCl3.) free radicals. This report details a series of experiments in which the effects of DMPG on CCl4 metabolism was evaluated in the rat. These data indicate that pretreatment with DMPG may reduce the hepatic concentration of the toxic CCl3. free radicals in CCl4 poisoned rats. Evidence is presented which suggests that this reduction in binding may have been due to a decrease in the rate of CCl4 metabolism. However, DMPG did not affect the hepatic concentration of total microsomal cytochrome P450, the necessary enzyme in this metabolic process. On the other hand, free radical spin trapping experiments indicate that the rate of free radical formation from CCl4 was slowed by treatment. Also, indirect evidence suggests that the metabolism of another cytochrome P450 substrate, phenobarbital, was slowed in DMPG treated rats. We conclude that the rate of CCl4 metabolism may be reduced by pretreatment with DMPG. Furthermore, some measure of hepatic protection might be expected to occur as a result of the reduction in the rate of CCl4 metabolism. However, we are unable to determine if this action was solely responsible for the observed hepatic protection.