Induction of Cytochrome P 450b and Its Relationship to Liver Tumor Promotion

A wide variety of compounds was examined for the ability to induce a specific form of hepatic cytochrome P 450 and to promote the development of DEN-initiated liver tumors (adenomas and carcinomas) in rats over a 72 week period. The induction of cytochrome P 450b was determined indirectly by measuring the hepatic induction of pentoxy-or benzyloxyresorufin O-dealkylase activities, which are highly specific substrates for the major phenobarbital-inducible forms of cytochrome P 450 in the rat. (10) Results in the rat showed: (1) potent inducers (> 40 ×) of P 450b (i.e., phenobarbital, barbital, ethylphenyl-hydantoin, and DDT) are all potent liver tumor promoters; (2) structural analogs that are not inducers of P 450b (i.e., hexobarbital, monoethylbarbituric acid, monophenyl-barbituric acid, and diethylhydantoin) all fail to display significant liver tumor promoting activity; and (3) the concomitant induction of liver hypertrophy, microsomal epoxide hydrolase, and cytochrome P 450b appears to be proportional and argues for some coordinated “pleiotropic” response of liver parenchyma to these inducers. Additional studies showed that phenobarbital induced cytochrome P 450b and was a liver tumor promoter not only in rats, but also in mice and patas monkeys, but was inactive as an enzyme inducer and was a nonpromoter in the hamster.