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 (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 ...Continue Reading
References
May 5, 1982·Journal of Molecular Biology·A M Gronenborn, G M Clore
Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Feb 1, 1997·Archives of Biochemistry and Biophysics·K I NodlandS Safe
Feb 27, 1999·Current Opinion in Biotechnology·G C Roberts
Sep 30, 1999·Cancer Letters·E G Snyderwine
Dec 2, 1999·Journal of the National Cancer Institute·A E NorrishR T Jackson
Jul 25, 2000·Toxicology Letters·Y ChenT G O'Brien
Dec 21, 2000·Cancer Letters·T KawamoriK Wakabayashi
Mar 30, 2001·The Journal of Biological Chemistry·M GangloffD Moras
Mar 29, 2002·Environmental and Molecular Mutagenesis·Elizabeth G Snyderwine
Apr 9, 2002·The Journal of Biological Chemistry·Anette WärnmarkAshley C W Pike
Aug 2, 2002·Toxicological Sciences : an Official Journal of the Society of Toxicology·Grantley D CharlesEdward W Carney
Dec 3, 2002·Journal of Medicinal Chemistry·Brad R HenkeMillard H Lambert
Dec 11, 2002·Mutagenesis·Elizabeth G SnyderwineMinshu Yu
Jun 27, 2003·Journal of Medicinal Chemistry·Johanne RenaudWilhelm Stark
May 3, 2005·The Journal of Steroid Biochemistry and Molecular Biology·Véronique St-LaurentAndré Tremblay
Jun 24, 2005·Nutrition Reviews·Mark G Knize, James S Felton
Apr 30, 1998·The Journal of Physical Chemistry. B·A D MacKerellM Karplus
Citations
Mar 18, 2008·Nature Chemical Biology·Kendall W NettlesGeoffrey L Greene
Sep 8, 2010·SAR and QSAR in Environmental Research·A R CunninghamJ O Trent
May 9, 2012·Obstetrics and Gynecology International·An T Vo, Richard M Millis
Jul 13, 2012·Environmental Health : a Global Access Science Source·Aleksandra FucicDomenico F Merlo
Dec 25, 2010·Arhiv za higijenu rada i toksikologiju·Jelena KatićMarija Gamulin
Jan 12, 2010·Cellular and Molecular Life Sciences : CMLS·Albane le MairePatrick Balaguer
Dec 29, 2009·Toxicology in Vitro : an International Journal Published in Association with BIBRA·Richard M EvansAndreas Kortenkamp
May 26, 2009·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Susanna C LarssonAlicja Wolk
Aug 6, 2008·Toxicology and Applied Pharmacology·Päivi MyllynenKirsi H Vähäkangas
Dec 2, 2011·Journal of Applied Toxicology : JAT·Dojung KimHae-Seong Yoon
Aug 4, 2009·Chemico-biological Interactions·E ImmonenP Myllynen
Jun 1, 2014·Toxicology Letters·M D PapaioannouN J Gooderham
Sep 13, 2011·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Malgorzata Kurzawa-ZegotaDiana Anderson
Sep 2, 2010·Toxicologic Pathology·Alexsandra FucicDomenico Franco Merlo
May 23, 2014·The American Journal of Clinical Nutrition·Zaynah AbidRashmi Sinha
Aug 2, 2008·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Eleni LinosLindsay A Frazier
Oct 3, 2007·Cancer Research·Sandra N Lauber, Nigel J Gooderham
Dec 7, 2007·Cancer Research·Stuart K CretonNigel J Gooderham
Sep 22, 2006·The Journal of Nutrition·James S Felton, Michael A Malfatti
Sep 2, 2008·Chemical Research in Toxicology·Albert R CunninghamSuzanne L Cunningham