The Interaction of Equol and Genistein on Estrogen Dependent Tumors and Bones in Ovariectomized Athymic Nude Mice

Song, Huaxin

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Description

Title

The Interaction of Equol and Genistein on Estrogen Dependent Tumors and Bones in Ovariectomized Athymic Nude Mice

Author(s)

Song, Huaxin

Issue Date

2008

Doctoral Committee Chair(s)

Murphy, Michael

Department of Study

Food Science and Human Nutrition

Discipline

Food Science and Human Nutrition

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

Biology, Biostatistics

Language

eng

Abstract

Experiments were conducted to evaluate the possible effects of dietary equol, one of the metabolites of daidzein, with and without genistein on human estrogen dependent tumor growth and bone development in ovariectomized athymic nude mice. In the first study, the experiments were conducted to evaluate the effect of equol alone on the T47D human breast cancer cells and bone metabolism. At the physiological concentration levels, 100 nM equol stimulated the T47D cell proliferation similarly as 0.1 nM 17-beta-estradiol in vitro. However, 250 ppm and 750 ppm dietary equol, which gave the total plasma equol concentrations (95% CI) 2.24+/-1.0 muM and 6.84+/-2.41 muM respectively, didn't affect either the tumor growth or bone metabolism compared with placebo control diet in OVX athymic mice. Then the interaction between equol and genistein was evaluated using MCF-7 human breast cancer cells. Equol and genistein both stimulated MCF-7 cell proliferation at physiological concentration levels (10-8--10-5 muM) in vitro. The diets containing 500 ppm genistein, 500 ppm genistein plus 250 ppm equol, 500 ppm genistein plus 500 ppm equol and 500 ppm genistein plus 1000 ppm equol stimulated MCF-7 tumor growth in OVX athymic mice similarly during 18 weeks treatment. There was no significant difference (p >0.1) on the final tumor size and mammary terminal end buds number for the treatment groups. To explain the lack of activity for equol in vivo, two pharmacokinetic studies on equol and equol plus genistein were conducted. No interaction between equol and genistein on their absorption and elimination was found. The half-life times of plasma total equol and total genistein (both conjugate and aglycone forms) were 1.18+/-0.24 hours (mean +/- STD) and 1.57+/-0.16 hours (mean +/- STD), respectively. The average aglycone forms of equol and genistein at 0.5h, 1h, 2h and 4h were approximately 0.5% and 5.6% of their total concentration, respectively. The half-life time for genistein aglycone was 3.66 hours, which was more than double of EQ aglycone (1.44 hours). Low concentration and short half-life time of equol aglycone form caused low activity of equol in vivo. The last part of my study was focus on using mathematical modeling to simulate the tumor growth and classify the characteristics of the tumors stimulated by genistein and genistein plus equol. Approximately, 66% of the growing tumors, which had at least one fold increase than their initial tumor size, would have two growing phase. The average time for tumors treated with genistein entering the late exponential growing phase was slightly shorter than genistein plus equol treated ones (18.20+/-4.04 vs. 21.28+/-4.70, p=0.0529). Most of the tumors with the second growth phase would have lower response to estrogen than the original MCF-7 cells. Also, these tumors with increased response to genistein and equol had correlated decreased response to tamoxifen. This suggested that genistein or genistein plus equol may induce the estrogen dependent tumor to be estrogen independent through some pathways other than estrogen regulated ones. Future studies on these genistein or isoflavones regulated pathways may help us understand the association between diet factors and estrogen independent tumors.

Graduation Semester

2008

Type of Resource

text

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