Phenobarbital (PB) has been shown to promote hepatic and thyroid neoplasia in carcinogen-initiated rats, while other structural analogs, including 5,5-dimethylbarbituric acid and the oxazolidinedione anticonvulsants, trimethadione and dimethadione, were negative in this respect. The latter compounds were also ineffective as inducers of hepatic CYP2B1 and CYP3A1. These results provide further evidence that CYP2B1 induction is strongly associated with liver and thyroid tumor promotion in the rat. A study of the pleiotropic hepatic response displayed by the rat to phenobarbital demonstrated that this response is also elicited by a variety of structurally-diverse phenobarbital-type CYP2B1 inducers. A rat line (Zucker) which has a defect with regard to its CYP2B1 reponsiveness to phenobarbital-type inducers was investigated for responsiveness to induction of other manifestations of the pleiotropic response (including epoxide hydrolase, testosterone 16 beta- hydroxylase). The induction of these drug metabolizing enzymes in two species of monkeys (Erythrocebus patas and Macaca fascicularis) was investigated and found to be qualitatively similar to that displayed by the rat (see project ZO1CP05092). Investigation of the ability of relatively low concentrations of the polychlorinated biphenyl mixture Aroclor 1254 to induce CYP1A protein and catalytic activity was investigated in laboratory rats fed Aroclor in the diet and in feral rodents (Reithrodontomys fulvescens) exposed environmentally to Aroclor.
