title: Apiaceous vegetable constituents inhibit human cytochrome P-450 1A2 (hCYP1A2) activity and hCYP1A2-mediated mutagenicity of aflatoxin B1.
abstract: In humans, apiaceous vegetables (carrots, parsnips, celery, parsley, etc.) inhibit cytochrome P-450 1A2, a biotransformation enzyme known to activate several procarcinogens, including aflatoxin B1 (AFB). We evaluated eight phytochemicals from apiaceous vegetables for effects on human cytochrome P-450 1A2 (hCYP1A2) activity using a methoxyresorufin O-demethylase (MROD) assay and a trp-recombination assay. Saccharomyces cerevisiae was used for heterologous CYP1A2 expression and this yeast strain is also diploid and auxotrophic for tryptophan due to mutations in the trp5 alleles. When these two alleles undergo AFB-induced mitotic recombination, gene conversion occurs, allowing yeast to grow in the absence of tryptophan. The apiaceous constituents psoralen, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), and apigenin were potent inhibitors of hCYP1A2-mediated MROD activity in yeast microsomes, whereas quercetin was a modest hCYP1A2 inhibitor. Naringenin, caffeic acid, and chlorogenic acid did not inhibit hCYP1A2-mediated MROD activity. The 2-h pretreatment of intact yeast cells with psoralen, 5-MOP, and 8-MOP significantly improved cell survival after subsequent 4-h AFB treatment and reduced hCYP1A2-mediated mutagenicity of AFB. Apigenin also significantly decreased mutagenicity. These results suggest that in vivo CYP1A2 inhibition by apiaceous vegetables may be due to the phytochemicals present and imply that apiaceous vegetable intake may be chemopreventive by inhibiting CYP1A2-mediated carcinogen activation.
authors.affiliation: Interdisciplinary Graduate Program in Nutritional Sciences, University of Washington, and Fred Hutchinson Cancer Research Center, Seattle, WA 98195-4695, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Peterson
authors.forename: Johanna W
authors.initials: JW
authors.lastname: Lampe
authors.forename: Theo K
authors.initials: TK
authors.lastname: Bammler
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gross-Steinmeyer
authors.forename: David L
authors.initials: DL
authors.lastname: Eaton
mesh_terms: D016604:Aflatoxin B1 / Q000493:pharmacokinetics* / Q000633:toxicity; D019661:Apiaceae / Q000737:chemistry; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D011564:Furocoumarins / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009153:Mutagens / Q000493:pharmacokinetics* / Q000633:toxicity; D010088:Oxidoreductases / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011042:Poisons / Q000493:pharmacokinetics* / Q000633:toxicity; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics
chemical_list: D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011564:Furocoumarins; D009153:Mutagens; D010936:Plant Extracts; D011042:Poisons; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; D019388:Cytochrome P-450 CYP1A2