title: Co-mutagenicity of coumarin (1,2-benzopyrone) with aflatoxin B1 and human liver S9 in mammalian cells.
abstract: Coumarin (1,2-benzopyrone), a natural dietary constituent and drug currently under evaluation for treatment of certain cancers and lymphedema, reduces polycyclic aromatic hydrocarbon-induced neoplasms in rodents. Because most rodents metabolize coumarin through 3,4-epoxidation, whereas 7-hydroxylation predominates in humans, their suitability as a model for coumarin effects in humans has been questioned. We examined coumarin chemoprotection against the promutagen and dietary contaminant aflatoxin B1 with human liver S9 bioactivation in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay. Coumarin in the absence of aflatoxin B1 was not mutagenic or cytotoxic up to 500 microM. When included with either 1 or 10 microM aflatoxin B1, coumarin produced a dose-dependent increase in mutant frequency and cytotoxicity. At concentrations greater than 50 microM, coumarin stimulated human liver S9 bioactivation of aflatoxin B1 to the mutagenic 8,9-epoxide. This increase was 12- and fivefold at 500 microM coumarin with 1 and 10 microM aflatoxin B1, respectively, compared with incubations with aflatoxin B1 alone. These findings differ from previous results with liver S9 from other species, and indicate that coumarin co-mutagenicity with aflatoxin B1 and human liver S9 is through increased aflatoxin B1 bioactivation.
authors.affiliation: Department of Preventive Medicine & Community Health, University of Texas Medical Branch, Galveston 77555-1109, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Goeger
authors.forename: A W
authors.initials: AW
authors.lastname: Hsie
authors.forename: K E
authors.initials: KE
authors.lastname: Anderson
mesh_terms: D016604:Aflatoxin B1 / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D016466:CHO Cells; D002478:Cells, Cultured; D003374:Coumarins / Q000633:toxicity*; D006224:Cricetinae; D004357:Drug Synergism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*
chemical_list: D003374:Coumarins; D009153:Mutagens; D016604:Aflatoxin B1; C030123:coumarin