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

Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77025

The cytochrome P-450-dependent drug metabolism system activities of rat colon microsomes are increased by gastrointestinal hormones. Pentagastrin, secretin, and cholecystokinin octapeptide increase the specific content of cytochrome P-450 over control and stimulate N-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 µg/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 4-fold 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 hormones, 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, 16,16-dimethylprostaglandin E₂ induces benzphetamine hydroxylation 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.

¹ This investigation was supported by Grant CA19105 awarded through the National Large Bowel Cancer Project of the National Cancer Institute, Department of Health, Education, and Welfare. A preliminary report of part of this investigation has been presented (9, 33).

² Recipient of Research Career Development Award 1-K04-CA00311 from the National Cancer Institute, Department of Health, Education, and Welfare. To whom requests for reprints should be addressed.

Received 10/ 7/80. Accepted 1/12/81.

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