P-450 Enzyme Induction by 5-Ethyl-5-phenylhydantoin and 5,5-Diethylhydantoin, Analogues of Barbiturate Tumor Promoters Phénobarbitaland Barbital, and Promotion of Liver and Thyroid Carcinogenesis Initiated by 7V-Nitrosodiethylamine in Rats1

Male F344/NCr rats, 6 wk old, were fed 500 ppm of phénobarbital (PB) or equimolar doses of either 5-ethyl-5-phenylhydantoin (EPH) or 5,5-diethylhydantoin (EEH) in diet for 2 wk and hepatic cytochrome P450-mediated alkoxyresorufm 0-dealkylase and aminopyrine A'-demethylase activities were determined. Both PB and EPH greatly increased P450-mediated enzyme activities in rat liver while EEH was ineffective. To evaluate the hydantoins as tumor promoters, 5-wk-old male F344 rats were given a single i.p. injection of 75 mg /V-nitrosodiethylamine/kg body weight. Beginning 2 wk later, they were placed either on normal diet or diet containing 500 ppm of PB or equimolar doses of EPH or EEH for the remaining experimental period. Control groups received an i.p. injec tion of saline followed by each of the test diets. Animals were sacrificed at either 52 or 78 wk. PB and EPH significantly enhanced the develop ment of hepatocellular foci and hepatocellular adenomas at 52 wk and hepatocellular carcinomas at 78 wk in /V-nitrosodiethylamine-initiated rats. Neither the incidence of hepatocellular neoplasms nor the number and size of hepatocellular foci was significantly increased by EEH. At 78 wk, both PB and EPH enhanced the development of thyroid follicular cell neoplasms in /V-nitrosodiethylamine-initiated rats while no such enhancement was observed with EEH. Thus, EPH, a long-acting sedative/ anticom ulsant, like the structurally similar PB, promoted hepatocellular and thyroid follicular cell carcinogenesis and induced the PB-inducible form(s) of cytochrome P-450 (P-450,,) in rats. In contrast, EEH unlike barbital failed to promote hepatocellular and thyroid follicular cell car cinogenesis and also failed to induce PB-inducible form(s) of cytochrome P-450 in rats.