As part of an investigation of the structural requirements for the induction, by
phenobarbital-type inducers, of a coordinate pleiotropic response consisting of increases in hepatic
cytochrome P450 2B (P450 2B) activity, increases in other phase I and II
enzyme activities, and liver
hypertrophy, we have examined a series of analogues of
phenobarbital in which the ethyl/phenyl substitution at the sp3
carbon of the parent molecule was kept constant while the heterocyclic portion of the molecule was modified. The induction of hepatic P450 2B
protein and ethoxy-, pentoxy-, and (benzyloxy)
resorufin O-dealkylation activities, and
epoxide hydration activity and liver/
body weight ratio increase were examined in male F344/NCr rats fed the various congeners for 14 days at doses equimolar to 500 ppm
phenobarbital. Increases in the measured parameters were maximal in rats fed
phenobarbital or
5-ethyl-5-phenylhydantoin. The responses to
primidone or 2-ethyl-2-phenylsuccinimide were approximately 65% of maximal, while
glutethimide yielded a response approximately 50% of maximal. Induction of this response in rats fed the ring-opened and decarboxylated analogues, (ethylphenylacetyl)
urea and
2-ethyl-2-phenylmalonamide, were < 25% of maximal.
5-Ethyl-5-phenyloxazolidinedione caused minimal increases in the measured end points when administered at a dose equimolar to 500 ppm
phenobarbital. The profound differences among the congeners in ability to induce P450 2B
protein and associated catalytic activities were not due to differences in food consumption by the various groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)