| 9918136 |
Williams JA, Stone EM, Millar BC, Gusterson BA, Grover PL, Phillips DH: Determination of the enzymes responsible for activation of the heterocyclic amine 2-amino-3-methylimidazo [4,5-f] quinoline in the human breast. Pharmacogenetics. 1998 Dec;8(6):519-28.
The heterocyclic amine 2-amino-3-methylimidazo [4,5-f] quinoline (IQ) is a potent mutagen and is a mammary carcinogen in rodents. In man, hepatic activation is carried out by cytochrome P450 (CYP) 1A2 and the ultimate DNA-reactive species is thought to be a nitrenium ion formed via an acetoxy ester of an exocyclic amino group. Because most human breast tumours are ductal in origin, we investigated the ability of cell types present in the mammary gland (breast epithelial cells and neutrophils present in milk) to activate IQ to DNA-binding species using 32P-postlabelling. Phorbol myristate acetate-stimulated neutrophils produced a similar pattern of IQ-DNA adducts to that produced by human mammary epithelial cells. Adduct formation in stimulated neutrophils was inhibited 80% by the myeloperoxidase inhibitor sodium azide (1 mM) but was not affected by proadifen (100 microM), indomethacin (100 microM), or eicosatetraynoic acid (100 microM), inhibitors of cytochrome P450, prostaglandin synthetase, and lipoxygenase, respectively. Similar experiments in human mammary epithelial cells showed no azide inhibition of IQ-DNA adduct formation. Analysis of gene expression by reverse transcription-polymerase chain reaction showed that CYP1A1 and CYP1B1, but not CYP1A2, were expressed at detectable levels in untreated mammary epithelial cells, whereas in neutrophils cytochrome P450 expression was confined to low levels of CYP1A1. In cultured epithelial cells, IQ-DNA adduct formation and CYP1A1, but not CYP1B1 expression were induced threefold by benz [a] anthracene treatment; IQ-DNA adduct formation was inhibited by alpha-naphthoflavone. Our results indicate possible mechanisms for the metabolic activation of dietary carcinogens in the human breast. |
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