Induction of estradiol 2-hydroxylase activity in MCF-7 human breast cancer cells by pesticides and carcinogens.
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abstract
The induction of 17-estradiol (E2) 2-hydroxylase activity was investigated in MCF-7 human breast cancer cells using 2-[(3)H]E2 as the substrate in a radiometric assay. Treatment of MCF-7 cells with 10 M indole-3-carbinol (I3C) for 48 h caused a 3.5-fold induction of E2 2-hydroxylase activity, whereas, I3C at concentrations as high as 100 M did not induce CYP1A1 mRNA levels or immunoreactive protein. Thus, the induction of E2 2-hydroxylase activity using the radiometric assay was not dependent on induction of CYP1A1. E2 2-hydroxylase activity was also increased by I3C within 2 h after treatment suggesting in situ interactions with the cellular cytochrome P450 system. The time-dependent effects of various chlorinated pesticides, antiestrogens and mammary carcinogens on E2 2-hydroxylase activity were also investigated. p,p'-DDE, atrazine and the mammary carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) significantly decreased E2 2-hydroxylase activity after 2 h; whereas, only the latter two compounds decreased activity after 48 h. Both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the mammary carcinogen benzo[a]pyrene (BaP) induced E2 2-hydroxylase in MCF-7 cells after incubation for 48 h and this was also paralleled by induction of CYP1A1 protein. The antiestrogens ICI 164384 and ICI 182780 decreased E2 2-hydroxylase activity in MCF-7 cells after incubation for 48 h, whereas tamoxifen and 4-hydroxytamoxifen were inactive. The results indicate that chemical-induced modulation of E2 2-hydroxylase activity in MCF-7 cells is complex and does not predict their activity as mammary carcinogens.
