Induction of hepatic cytochrome P450 2B (CYP2B) has proved to be an efficient and reliable interspecies predictor of promoting activity for hepatocellular neoplasms. This project is the focus for LCC studies on tumor promotion in non-squamous epithelia. As part of an effort to determine the structure-activity relationships for hepatic CYP2B induction, a series of ethyl/phenyl substituted phenobarbital congeners was examined in the F344/NCr rat. This study, in combination with in vivo and in vitro pharmacodynamic studies, has demonstrated that phenobarbital and 5-ethyl-5-phenylhydantoin are equipotent at inducing CYP2B activity in the rat, while 5-ethyl-5-phenyloxazolidinedione is approximately an order of magnitude less potent for this effect. These results not only provide clues regarding the active site concentration-CYP2B induction response relation-ships, but also serve to validate the use of hepatocyte cultures for this kind of study. Based upon examination of immunoreactive CYP2B1 and CYP2B2 protein and CYP2B-mediated catalytic activities, it was found that the degree of induction of CYP2B by phenobarbital in the female rat is as great as or greater than that in the male rat. However, the potency of phenobarbital for inducing this effect is lower in the female rat, as indicated by the greater EC50. Additional studies have demonstrated that the pleiotropic response observed in F344/NCr rats exposed to phenobarbital-type inducers is also displayed by rabbits, mice and hamsters. No qualitative differences in this response were observed among eight different inbred strains of rats. 1,4-Bis[2-(3,5- dichloropyridyloxy)]benzene (TCPOBOP) was shown to exert a complete carcinogenic effect and a tumor promoting effect in both DBA/2 and C57BL/6 mice; however, this chemical was ineffective as a carcinogen or tumor promoter in the F344/NCr rat. The marked species difference in the promotion response to TCPOBOP correlated with the hepatic microsomal enzyme induction displayed in the two species in that the compound was a very effective CYP2B inducer in mice but yielded only weak induction in the rat at the dose levels examined (see also project Z01CP05352).
