Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat.
Earlier studies showed that phenobarbital feeding enhanced hepatic tumorigenesis in rats previously fed 2-acetylaminofluorene for a brief period. As part of an investigation of the mechanism of this enhancement, the present study evaluated the relative enhancing abilities of amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane (DDT), agents that resemble phenobarbital to varying degrees in their effects on liver structure and metabolism. A comparison of hepatic tumor yields in rats fed 2-acetylaminofluorene, followed by the test substance (sequential treatment), showed that amobarbital and diphenylhydantoin had no enhancing activity, whereas the enhancing effect of DDT was similar to that of phenobarbital. These results show that the sequential treatment technique readily distinguishes among substances differing in enhancing ability and should prove useful in screening additional substances for this activity. The comparative biochemical effects of these substances in the liver can then be correlated with their relative enhancing abilities to provide information on the molecular events specifically associated with enhancement. Such correlations were initiated in this study by comparing the effects of the four test substances on liver weight and DNA synthesis. The results showed that the enhancers, phenobarbital and DDT, each stimulated liver DNA synthesis and increased liver weight, whereas the nonenhancers, amobarbital and diphenylhydantoin, had neither effect. Phenobarbital and DDT both increased the early tumor incidence rate and maintained an increment in tumor incidence over that in the other treatment groups throughout the experiment, although it is not clear whether this increment would persist indefinitely. In addition, although the spectrum of tumor types observed ranged from highly differentiated to poorly differentiated in all treatment groups, DDT and phenobarbital selectively increased the incidence of highly differentiated tumors throughout most of the experiment.