Role of colonic cytochrome P-450 in large bowel carcinogenesis.

Rat colon mucosa microsomes contain a competent mixed function oxidase system that hydroxylates the N-methyl drugs benzphetamine and ethylmorphine, the O-alkyl drugs p-nitroanisole and p-nitrophenetole and the polycyclic carcinogen benzo[alpha]pyrene. The colon system's hydroxylation activities can be selectively induced by pretreatment with phenobarbital or beta-naphthoflavone and can be selectively inhibited by SKF-525A or 7,8-benzoflavone. The colon microsomal system has been solubilized with the non-ionic detergent Renex 690 and resolved by column chromatography into its components cytochrome P-450 and cytochrome P-450 reductase. Colon cytochrome P-450 and cytochrome P-450 reductase can be recombined to reconstitute hydroxylation activity. The colon system is also able to activate carcinogens to mutagenic metabolites as demonstrated in the Ames test system. In addition, the activity of the colon system is markedly increased by pretreatment with gastrointestinal hormones.