Effects of heterocyclic amines with mammary gland carcinogenic potential on estrogenic response of uterus in ovariectomized rats

Kawamori, Toshihiko; Uchiya, Naoaki; Watanabe, Kouji; Ohta, Toshihisa; Sügimura, Takashi; Wakabayashi, Keiji

doi:10.1016/s0304-3835(00)00626-1

Cited by 7 publications

(2 citation statements)

References 18 publications

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“…Gooderham and coworkers have also shown that the pure anti-estrogen ICI 182,780 abolishes PhIP transcriptional activity, further suggesting that PhIP binds specifically to ERR (28). However, in studies on ovarectomized Sprague-Dawley rats, PhIP did not produce any estrogenic response (29), suggesting that PhIP is not a strong estrogen mimic in this assay system. Other studies propose that PhIP promotes carcinogenesis by retarding mammary gland development (30), increasing serum prolactin levels (31), and inhibiting apoptosis (32).…”

Section: Introductionmentioning

confidence: 92%

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor

Bennion

Cosman

Lightstone

et al. 2005

Chem. Res. Toxicol.

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Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here, we describe our work with the human estrogen receptor alpha (ERalpha), the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, and IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We demonstrate both by computational docking and NMR analysis that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. In vitro assays show that PhIP, in contrast to the other heterocyclic amines, increases cell proliferation in MCF-7 human breast cancer cells and activates the ERalpha receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ERalpha activation. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat breast tumors and the presumptive human breast cancer associated with the consumption of well-done meat maybe mediated by this receptor activation.

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Section: Introductionmentioning

confidence: 92%

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor

Bennion

Cosman

Lightstone

et al. 2005

Chem. Res. Toxicol.

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show abstract

“…Gooderham and coworkers have also shown that the pure anti-estrogen ICI 182,780 abolishes PhIP transcriptional activity, further suggesting that PhIP binds specifically to ERα (Lauber et al, 2004). However, in studies on ovarectomized Sprague-Dawley rats, PhIP did not produce any estrogenic response (Kawamori et al, 2001), suggesting that PhIP is not a strong estrogen mimic in this assay system. Other studies propose that PhIP promotes carcinogenesis by retarding mammary gland development (Snyderwine et al, 1998), increasing serum prolactin levels (Venugopal et al, 1999b) and inhibiting apoptosis (Venugopal et al, 1999a).…”

Section: Tif2 Helixmentioning

confidence: 92%

Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors

Bennion¹,

Kulp²,

Cosman³

et al. 2005

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. (From -To) Aug 1 REPORT DATE (DD-MM-YYYY) 01-09-2005 REPORT TYPE Final Report DATES COVERED PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBE RRegents of the University of California Lawrence Livermore Natl. Lab.7000 East Ave Livermore California 94550 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STAT EMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES 314. ABSTRACT Many carcinogens have been shown to cause tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and is usually attributed to differences in organ metabolism. For heterocyclic amines, potent carcinogens that are formed in well-done meat, the ability to either bind to the estrogen receptor and activate or inhibit an estrogenic response will have a major impact on carcinogenicity. Here we describe our work with the human estrogen receptor alpha (hERa) and the mutagenic/carcinogenic heterocyclic amines PhIP, MeIQx, IFP, and the hydroxylated metabolite of PhIP, N2-hydroxy-PhIP. We found that PhIP, in contrast to the other heterocyclic amines, increased cell-proliferation in MCF-7 human breast cancer cells and activated the hERa receptor. We show mechanistic data supporting this activation both computationally by homology modeling and docking, and by NMR confirmation that PhIP binds with the ligand binding domain (LBD). This binding competes with estradiol (E2) in the native E2 binding cavity of the receptor. We also find that other heterocyclic amines and N2-hydroxy-PhIP inhibit ER activation presumably by binding into another cavity on the LBD. Moreover, molecular dynamics simulations of inhibitory heterocyclic amines reveal a disruption of the surface of the receptor protein involved with protein-protein signaling. We therefore propose that the mechanism for the tissue specific carcinogenicity seen in the rat breast tumors and the presumptive human brea...

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Responses of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in MCF-7 cells are culture condition dependent

Immonen

Serpi

Vähäkangas

et al. 2009

Chemico-Biological Interactions

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Effects of heterocyclic amines with mammary gland carcinogenic potential on estrogenic response of uterus in ovariectomized rats

Cited by 7 publications

References 18 publications

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor

PhIP Carcinogenicity in Breast Cancer: Computational and Experimental Evidence for Competitive Interactions with Human Estrogen Receptor

Computational Characterization and Prediction of Estrogen Receptor Coactivator Binding Site Inhibitors

Responses of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in MCF-7 cells are culture condition dependent

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