Abstract

The hepatic tumors studied in this paper are either devoid of or deficient in their ability to metabolize certain drugs which are metabolized by microsomal enzyme systems in normal liver. Both "minimal deviation" rat hepatomas and the " multiple deviation" Novikoff hepatoma were investigated also for their ability to respond to agents which stimulate the activity of these microsomal systems in normal liver. The "minimal deviation" hepatomas were shown to have some activity for most of the drug pathways studied, and further were able to respond with increased enzyme activity when the host animals were pretreated with phenobarbital. No metabolism of aminopyrine, aniline, p-nitro-benzoic acid, or hexobarbital could be detected in the Novikoff hepatoma. After treatment with phenobarbital of rats bearing the Novikoff tumor, only the metabolism of hexobarbital by the tumor was even slightly increased. It was further shown that phenobarbital, 3 hours after a single dose, was present in the hepatoma 5123B in concentrations comparable to those measured in the host liver and blood.

Rats fed the hepatic carcinogen, 4-dimethyl-aminoazobenzene (DAB), were removed from this diet at intervals varying from 3 to 10 months after beginning the diet and then treated with phenobarbital. In nearly all livers from such DAB-fed rats there were increases in microsomal drug metabolizing enzyme activity comparable to those seen in phenobarbital treated control animals. This was true whether the liver tissue was directly adjacent to DAB-induced hepatic tumors or was far removed therefrom. In DAB-induced tumors, phenobarbital caused a stimulation of hexobarbital metabolizing activity, but had no appreciable effect on the metabolism of aminopyrine.

The ability of the drug metabolizing enzymes to respond to enzyme inducers was discussed with regard to the "deletion" theory of carcinogenesis.