title: Effects of chemoprotective agents on the metabolic activation of the carcinogenic arylamines PhIP and 4-aminobiphenyl in human and rat liver microsomes.
abstract: Carcinogenic aromatic amines, including the heterocyclic amines, may pose a significant health risk to humans. To determine the potential for chemoprotective intervention against the carcinogenicity of these arylamines and to better understand their mechanism of action, a range of agents, most of them natural dietary constituents, was examined in vitro for their ability to modulate the N-hydroxylation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 4-aminobiphenyl (ABP), an initial step in their bioactivation. Experiments were conducted with rat and human liver microsomes. The agents (diallyl sulfide, indole-3-carbinol, alpha-angelicalactone, cafestol/kahweol palmitates, cafestol, kahweol, benzylisothiocyanate, genistin, formononetin, daidzin, equol, biochanin A, Oltipraz, tannic acid, quercetin, ethoxyquin, green tea, and black tea) comprised a variety of chemical classes that included sulfur-containing compounds, antioxidants, flavonoids, phytoestrogens, diterpenes, and polyphenols. Several of these agents, quercetin, ethoxyquin, and black tea, were found to strongly inhibit PhIP N-hydroxylation in rat liver microsomes, resulting in a nearly 85-90% decrease in activity at 100 microM or 0.2%. Tannic acid and green tea, in addition to these agents, were also strong inhibitors of ABP N-hydroxylation. In human liver microsomes, each of these agents was strongly inhibitory (approx 85-95% at 100 microM or 0.02%) of PhIP and ABP N-hydroxylation. Theaflavins and polyphenols were judged to be the primary inhibiting components in the teas, the theaflavins showing the most potent effect. These results demonstrate that chemoprotective agents can inhibit the bioactivation of carcinogenic arylamines, and this is likely to be one of the mechanisms of protection.
authors.affiliation: Division of Molecular Epidemiology, National Center of Toxicological Research, Jefferson, AR 72079, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Hammons
authors.forename: J V
authors.initials: JV
authors.lastname: Fletcher
authors.forename: K R
authors.initials: KR
authors.lastname: Stepps
authors.forename: E A
authors.initials: EA
authors.lastname: Smith
authors.forename: D A
authors.initials: DA
authors.lastname: Balentine
authors.forename: M E
authors.initials: ME
authors.lastname: Harbowy
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D007529:Isoflavones; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology; D048789:Phytoestrogens; D028321:Plant Preparations; D011108:Polymers / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000611:Aminobiphenyl Compounds; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D002273:Carcinogens; D004224:Diterpenes; D004968:Estrogens, Non-Steroidal; D005419:Flavonoids; D007093:Imidazoles; D007529:Isoflavones; D010636:Phenols; D048789:Phytoestrogens; D028321:Plant Preparations; D011108:Polymers; C006757:4-biphenylamine; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine