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Novel Cytochrome P45O1B1 as a Mammary Cancer Risk Factor.
Annual rept. 1 Jul 96-30 Jun 97,
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A recent report has confirmed our hypothesis that CYP1B1 is a gene that can regulate organ development. In the past year, we have established quantitation of the very low levels of CYP1B1 and CYPlAl in cultured breast epithelia from 7 donors. Metabolism of 7,1 2-dimethylbenzaanthracene in these cells is initially due to CYP1B1 in 5 of 7 donors, but CYP1A1 contribute about half of the activity for 2 donors. Prolonged exposure to the DMBA or pre-exposure to the environmental toxicant dioxin elevated the total activity and contribution of the much more active CYP1A1. Turnover numbers and product selectivity for these forms for DMBA were comparable to what we observed for recombinant human CYP1B1 and CYP1A1. Equivalent analyses are being completed for estradiol. DNA adducts from dibenzoalpyrene and the 11,12 dihydrodiol were measured in HBEC from 3 donors. Dihydrodiol epoxide adducts to dA and dO were similar for each donor under conditions where complete metabolism had occurred. We have established that 2-ethynylphenanthrene 2.5 M and meffiyl-1-ethynyl pyrene 2.5 M are selective inhibitors of respectively CYP1B1 and CYP1A1. Cultured HB fibroblasts HBF, but not the epithelia, expressed normal estrogen receptors. Growth of HBF was stimulated by estradiol E2 which may, therefore, mediate efforts of E2 on epithelia. HBF expressed CYP1B1 but not CYP1A1 and differed substantially between donors in this respect, suggesting individual differences in regulation.
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