title: Bile acid inhibition of xenobiotic-metabolizing enzymes is a factor in the mechanism of colon carcinogenesis: tests of aspects of the concept with glucuronosyltransferase.
abstract: A factor in colon carcinogenesis might be the partial defeat in colon epithelial cells of the protective enzymic barrier against xenobiotics, via bile acid inhibition of enzymes that detoxify mutagens. The applicability of aspects of this concept to glucuronosyltransferase, a phenol detoxification enzyme, was tested in a colon cancer cell line. Inhibition of glucuronidation of the test substrate, 4-methylumbelliferone, occurred at bile acid concentrations found in faecal water, and depended on pH for some bile acids. Lithocholate was the most inhibitory: the concentration causing 50% inhibition of the initial rate of glucuronidation (IC50) was about 3 microM at pH 7.4 and at pH 6.2. The inhibitory potency of deoxycholate and chenodeoxycholate increased when pH decreased, but still remained less than that of lithocholate: the IC50 for deoxycholate was 88.5 microM at pH 7.4, and 14.8 microM at pH 6.2, and for chenodeoxycholate the IC50 was 67.4 microM at pH 7.4, and 21.7 microM at pH 6.2. Cholate did not cause appreciable inhibition. The inhibitory effects were additive when lithocholate was present together with either deoxycholate or chenodeoxycholate. The results provide a mechanism for the comutagenicity of bile acids, a feature of which is the inter-relation of bile acid comutagenicity specifically with mutagens that are inactivated by a bile acid-inhibitable enzyme. The results are also in accord with the view that high concentrations of bile acids in solution in faecal water, especially lithocholate, are a risk factor for colon cancer.
authors.affiliation: Institute for Biological Sciences, National Research Council of Canada, Ottawa.
authors.forename: H
authors.initials: H
authors.lastname: Schneider
authors.forename: H
authors.initials: H
authors.lastname: Fiander
authors.forename: R K
authors.initials: RK
authors.lastname: Latta
authors.forename: N W
authors.initials: NW
authors.lastname: Ross
mesh_terms: D001647:Bile Acids and Salts / Q000494:pharmacology*; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D003106:Colon / Q000166:cytology / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005453:Fluorescence; D005456:Fluorescent Dyes; D005965:Glucuronates / Q000378:metabolism; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000494:pharmacology; D008095:Lithocholic Acid / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005965:Glucuronates; D015262:Xenobiotics; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; C024098:6-carboxyfluorescein; D006923:Hymecromone; D008095:Lithocholic Acid; C034888:4-methylumbelliferyl glucuronide; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase