This proposal is aimed at testing a novel hypothesis that chemicals that can preferentially stimulate the metabolic conversion of estradiol (E2) and its hydroxylated metabolites (such as 4-OH-E2 and 16alpha-OH-E1) to inactive, water-soluble conjugates would be better and safer inhibitors of E2-induced cancer than inducers of estrogen oxidative metabolism. On the basis of our recent data on the preferential stimulatory effect of dietary dibenzoylmethane (DAM) on E2 conjugative metabolism in human mammary cells and in animals, we propose the following four Specific Aims for our initial testing of this novel hypothesis.
Aim 1 : To study dietary DBM and its analogs for their activity in inducing the enzymes for estrogen conjugation (glucuronidation, sulfation, and O-methylation) vs oxidation in non-neoplastic AG11134 human mammary epithelial cells by using biochemical assays and Northern blot analysis.
Aim 2 : To study strong dietary inducers identified under Aim 1 for their activity in inducing estrogen conjugation in liver, breast, and uterus of female ACI rats.
Aim 3 : To compare the effects of strong inducers of estrogen conjugation with indole-3-carbinol (a prototypical dietary inducer of estrogen oxidation) on the metabolic fate of E2 and 4-OH-E2 (a representative bioactive hydroxyestrogen metabolite) in blood and target organs of female ACI rats.
Aim 4 : To compare the effects of an identified inducer of estrogen conjugative metabolism with indole-3-carbinol on the mitogenic actions of E2 and 4-OH-E2 in the breast and uterus of female rats, and to compare their efficacies in the prevention of estrogen-induced mammary tumors in female ACI rats. We predict that an inducer of estrogen conjugative metabolism will have a much higher cancer-preventive efficacy than an inducer of estrogen oxidative metabolism under conditions where estrogen's hormonal activity is equally inhibited. These hypothesis-driven, mechanism-based studies will lead to the development of an effective, novel strategy for dietary or phytochemical-based prevention of estrogen-induced human cancers. These studies will also provide examinations of the important roles of bioactive estrogen metabolites (e.g., 4-OH-E2 and 16alpha-OH-E2) in estrogen-induced cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092391-03
Application #
6853607
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Poland, Alan P
Project Start
2003-03-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$207,338
Indirect Cost
Name
University of South Carolina at Columbia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
111310249
City
Columbia
State
SC
Country
United States
Zip Code
29208
Zhu, Bao Ting (2010) On the general mechanism of selective induction of cytochrome P450 enzymes by chemicals: some theoretical considerations. Expert Opin Drug Metab Toxicol 6:483-94
Zhu, Bao Ting; Wang, Pan; Nagai, Mime et al. (2009) Inhibition of human catechol-O-methyltransferase (COMT)-mediated O-methylation of catechol estrogens by major polyphenolic components present in coffee. J Steroid Biochem Mol Biol 113:65-74
Fu, Xin-Miao; Zhu, Bao Ting (2009) Human pancreas-specific protein disulfide isomerase homolog (PDIp) is an intracellular estrogen-binding protein that modulates estrogen levels and actions in target cells. J Steroid Biochem Mol Biol 115:20-9
Zhang, Elizabeth Yan; Chen, Aaron Yun; Zhu, Bao Ting (2009) Mechanism of dinitrochlorobenzene-induced dermatitis in mice: role of specific antibodies in pathogenesis. PLoS One 4:e7703
Zhu, Bao Ting; Gallo, Michael A; Burger Jr, Conney W et al. (2008) Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice. Toxicol Appl Pharmacol 226:107-18
Bai, Hyoung-Woo; Shim, Joong-Youn; Yu, Jina et al. (2007) Biochemical and molecular modeling studies of the O-methylation of various endogenous and exogenous catechol substrates catalyzed by recombinant human soluble and membrane-bound catechol-O-methyltransferases. Chem Res Toxicol 20:1409-25
Zhu, Bao Ting; Han, Gui-Zhen; Shim, Joong-Youn et al. (2006) Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding. Endocrinology 147:4132-50
Zhu, Bao Ting; Lee, Anthony J (2005) NADPH-dependent metabolism of 17beta-estradiol and estrone to polar and nonpolar metabolites by human tissues and cytochrome P450 isoforms. Steroids 70:225-44
Lee, Anthony J; Zhu, Bao Ting (2004) NADPH-dependent formation of polar and nonpolar estrogen metabolites following incubations of 17 beta-estradiol with human liver microsomes. Drug Metab Dispos 32:876-83