Control by Gastrointestinal Hormones of the Hydroxylation of the Carcinogen Benzo(a)pyrene and Other Xenobiotics in Rat Colon1

The cytochrome P-450-dependent drug metabolism system activities of rat colon microsomes are increased by gastroin testinal hormones. Pentagastrin, secretin, and cholecystokinin octapeptide increase the specific content of cytochrome P-450 over control and stimulate /V-demethylation, O-dealkylation, and polycyclic aromatic hydrocarbon hydroxylation to different degrees. Increase in hydroxylation activity by pentagastrin is dose dependent with a stimulation of 250% of control occurring at a dose level of 250 fig/kg body weight. The increase in hydroxylation activity is prevented by cycloheximide treatment showing dependence on protein synthesis. Pentagastrin and cholecystokinin increase the specific content of colon microsomal P-450 77%, while secretin increases cytochrome P-450 content 138% of the control value. Pentagastrin induces a 4fold increase in ethylmorphine demethylation, while the major effect by secretin is on p-nitrophenetole dealkylation activity (2-fold increase), and the major effects of cholecystokinin are on benzphetamine and benzo(a)pyrene hydroxylation (2-fold induction). These hormones induce the hydroxylation of other substrates also, but the pattern of effects varies with the hormone used. Liver microsomal hydroxylation activities are also increased significantly by pretreatment with these hor mones, although to a lesser degree than colon hydroxylation activities. Several tissue substances induce the hydroxylation of specific substrates, although no pattern of inductive effects is evident. For example, reserpine pretreatment doubles the rate of benzo(a)pyrene hydroxylation in liver and colon microsomes but decreases or has no effect on other hydroxylation activities in liver microsomes and induces only ethylmorphine dealkylation in colon microsomes. On the other hand, 16,16dimethylprostaglandin E2 induces benzphetamine hydroxyl ation in the colon but only benzo(a)pyrene hydroxylation in the liver. The gastrointestinal hormones induce drug metabolism with an apparent pattern of specificities and an increase in cytochrome P-450 specific content not seen in animals pretreated with the tissue substances tested.