Induction of hepatic cytochrome P450 2B (CYP2B) would appear to be a reliable interspecies predictor of promoting activity for hepatocellular neoplasms. This project is the focus for LCC studies on tumor promotion in non-squamous epithelia. 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was found to be a profound phenobarbital-type inducer in the rat when administered in the diet for two weeks at 1000 ppm. When extent of induction was related to serum total xenobiotic level, TCPOBOP appeared to be at least as potent, if not more potent, than phenobarbital in the rat. This result, which was confirmed by studies performed with cultured rat hepatocytes, contradicted the commonly held assumption that TCPOBOP is ineffective as a CYP2B inducer in the rat. In other experiments performed with intact F344/NCr rats and primary rat hepatocyte cultures, the potencies for CYP2B induction of the racemate and the individual enantiomers of 5-ethyl-5-phenylhydantoin were found to be essentially equivalent. The induction of CYP2B activity in male B6C3F1 mice by phenobarbital congeners was investigated and compared to the induction in rats by the same compounds. An apparent species difference in relative inducing ability by phenobarbital and 5-ethyl-5- phenylhydantoin was found to reflect differences in pharmacokinetics, not intrinsic inducing ability of these compounds. A direct relationship between level of expression of hepatic drug metabolizing enzymes and polychlorinated biphenyl (PCB) burden in the liver of F344/NCr rats fed Aroclor 1254 was observed, irrespective of the type of exposure (continuous or discontinous). Distinctly different dose-response curves for the induced enzymes were detected, implying different dose thresholds for these effects, many of which are apparently subject to similar transcriptional control. The cotton rat (Sigmodon hispidus) was also found to be exceptionally sensitive to the P450-inducing effects of Aroclor 1254. The ability of phenytoin to promote hepatocellular neoplasia was investigated in D2B6F1 mice. This anticonvulsant elicited profound dose-dependent CYP2B induction and liver tumor promotion (see also project ZO1CP05352).
