{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:21:04Z","timestamp":1760235664101,"version":"build-2065373602"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T00:00:00Z","timestamp":1630886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["2018-1.2.1-NKP-2018-00005","\u00daNKP-20-4 NEW NATIONAL EXCELLENCE PROGRAM"],"award-info":[{"award-number":["2018-1.2.1-NKP-2018-00005","\u00daNKP-20-4 NEW NATIONAL EXCELLENCE PROGRAM"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Central European Leuven Strategic Alliance (CELSA)","award":["CELSA\/19\/017"],"award-info":[{"award-number":["CELSA\/19\/017"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Symmetry"],"abstract":"<jats:p>Conjugated estrogen medicines, which are produced from the urine of pregnant mares for the purpose of menopausal hormone replacement therapy (HRT), contain the sulfate conjugates of estrone, equilin, and equilenin in varying proportions. The latter three steroid sex hormones are highly similar in molecular structure as they only differ in the degree of unsaturation of the sterane ring \u201cB\u201d: the cyclohexene ring in estrone (which is naturally present in both humans and horses) is replaced by more symmetrical cyclohexadiene and benzene rings in the horse-specific (\u201cequine\u201d) hormones equilin and equilenin, respectively. Though the structure of ring \u201cB\u201d has only moderate influence on the estrogenic activity desired in HRT, it might still significantly affect the reactivity in potential carcinogenic pathways. In the present theoretical study, we focus on the interaction of estrogen orthoquinones, formed upon metabolic oxidation of estrogens in breast cells with purine nucleosides. This multistep process results in a purine base loss in the DNA chain (depurination) and the formation of a \u201cdepurinating adduct\u201d from the quinone and the base. The point mutations induced in this manner are suggested to manifest in breast cancer development in the long run. We examine six reactions between deoxyadenosine and deoxyguanosine as nucleosides and estrone-3,4-quinone, equilin-3,4-quinone, and equilenin-3,4-quinone as mutagens. We performed DFT calculations to determine the reaction mechanisms and establish a structure\u2013reactivity relationship between the degree of unsaturation of ring \u201cB\u201d and the expected rate of DNA depurination. As quinones might be present in the cytosol in various protonated forms, we introduce the concept of \u201ceffective barriers\u201d to account for the different reactivity and different concentrations of quinone derivatives. According to our results, both equine estrogens have the potential to facilitate depurination as the activation barrier of one of the elementary steps (the initial Michael addition in the case of equilenin and the rearomatization step in the case of equilin) significantly decreases compared to that of estrone. We conclude that the appearance of exogenous equine estrogen quinones due to HRT might increase the risk of depurination-induced breast cancer development compared to the exposure to endogenous estrone metabolites. Still, further studies are required to identify the rate-limiting step of depurination under intracellular conditions to reveal whether the decrease in the barriers affects the overall rate of carcinogenesis.<\/jats:p>","DOI":"10.3390\/sym13091641","type":"journal-article","created":{"date-parts":[[2021,9,6]],"date-time":"2021-09-06T23:55:22Z","timestamp":1630972522000},"page":"1641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Reactivity of Human and Equine Estrogen Quinones towards Purine Nucleosides"],"prefix":"10.3390","volume":"13","author":[{"given":"Zsolt","family":"Benedek","sequence":"first","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gell\u00e9rt t\u00e9r 4, H-1111 Budapest, Hungary"}]},{"given":"Peter","family":"Girnt","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gell\u00e9rt t\u00e9r 4, H-1111 Budapest, Hungary"}]},{"given":"Julianna","family":"Olah","sequence":"additional","affiliation":[{"name":"Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Szent Gell\u00e9rt t\u00e9r 4, H-1111 Budapest, Hungary"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"ESHRE Capri Workshop Group (2004). Hormones and breast cancer. Hum. Reprod. Update, 10, 281\u2013293.","DOI":"10.1093\/humupd\/dmh025"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1056\/NEJM200101253440407","article-title":"Estrogen and the Risk of Breast Cancer","volume":"344","author":"Clemons","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Million Women Study Collaborators (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362, 419\u2013427.","DOI":"10.1016\/S0140-6736(03)14065-2"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1056\/NEJMsr070105","article-title":"The Decrease in Breast-Cancer Incidence in 2003 in the United States","volume":"356","author":"Ravdin","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1196\/annals.1347.018","article-title":"Impact of Metabolism on the Safety of Estrogen Therapy","volume":"1052","author":"Prokai","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3181\/00379727-217-44199","article-title":"Pharmacokinetics and Pharmacodynamics of Conjugated Equine Estrogens: Chemistry and Metabolism","volume":"217","author":"Bhavnani","year":"1998","journal-title":"Exp. Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4857","DOI":"10.1210\/en.2008-0304","article-title":"Structure Activity Relationships and Differential Interactions and Functional Activity of Various Equine Estrogens Mediated via Estrogen Receptors (ERs) ER\u03b1 and ER\u03b2","volume":"149","author":"Bhavnani","year":"2008","journal-title":"Endocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12971","DOI":"10.1074\/jbc.M110.205112","article-title":"Exploration of Dimensions of Estrogen Potency","volume":"286","author":"Jeyakumar","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1021\/tx1001282","article-title":"Redox Cycling of Catechol Estrogens Generating Apurinic\/Apyrimidinic Sites and 8-oxo-Deoxyguanosine via Reactive Oxygen Species Differentiates Equine and Human Estrogens","volume":"23","author":"Wang","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_10","first-page":"4347","article-title":"Carcinogenic activities of various steroidal and nonsteroidal estrogens in the hamster kidney: Relation to hormonal activity and cell proliferation","volume":"55","author":"Li","year":"1995","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1093\/carcin\/21.3.427","article-title":"Hormonal carcinogenesis","volume":"21","author":"Henderson","year":"2000","journal-title":"Carcinogenesis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1126\/science.1106943","article-title":"A Transmembrane Intracellular Estrogen Receptor Mediates Rapid Cell Signaling","volume":"307","author":"Revankar","year":"2005","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1677\/erc.1.01322","article-title":"Role of receptor complexes in the extranuclear actions of estrogen receptor \u03b1 in breast cancer","volume":"13","author":"Song","year":"2006","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1093\/carcin\/bgg004","article-title":"Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: Potential biomarkers of susceptibility to cancer","volume":"24","author":"Rogan","year":"2003","journal-title":"Carcinogenesis"},{"key":"ref_15","first-page":"3146","article-title":"Tissue content of hydroxyestrogens in relation to survival of breast cancer patients","volume":"8","author":"Castagnetta","year":"2002","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1021\/tx8000797","article-title":"Problematic detoxification of estrogen quinones by NAD(P)H-dependent quinone oxidoreductase and glutathione-S-transferase","volume":"21","author":"Chandrasena","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1021\/tx700191p","article-title":"Potential Mechanisms of Estrogen Quinone Carcinogenesis","volume":"21","author":"Bolton","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1021\/tx800071u","article-title":"Mechanistic Insights into the Michael Addition of Deoxyguanosine to Catechol Estrogen-3,4-quinones","volume":"21","author":"Stack","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"475","DOI":"10.3390\/metabo5030475","article-title":"Identifying the Tautomeric Form of a Deoxyguanosine-Estrogen Quinone Intermediate","volume":"5","author":"Stack","year":"2015","journal-title":"Metabolites"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cavalieri, E.L., and Rogan, E.G. (2016). Depurinating estrogen-DNA adducts, generators of cancer initiation: Their minimization leads to cancer prevention. Clin. Transl. Med., 5.","DOI":"10.1186\/s40169-016-0088-3"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.bbcan.2006.03.001","article-title":"Catechol estrogen quinones as initiators of breast and other human cancers: Implications for biomarkers of susceptibility and cancer prevention","volume":"1766","author":"Cavalieri","year":"2006","journal-title":"Biochim. Biophys. Acta\u2013Rev. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1021\/tx980217v","article-title":"The Major Metabolite of Equilin, 4-Hydroxyequilin, Autoxidizes to an o -Quinone Which Isomerizes to the Potent Cytotoxin 4-Hydroxyequilenin- o -quinone","volume":"12","author":"Zhang","year":"1999","journal-title":"Chem. Res. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1093\/carcin\/18.5.1093","article-title":"Bioreductive activation of catechol estrogen-ortho-quinones: Aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity","volume":"18","author":"Shen","year":"1997","journal-title":"Carcinogenesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8633","DOI":"10.1074\/jbc.M807860200","article-title":"Estrogen Receptor \u03b1 Enhances the Rate of Oxidative DNA Damage by Targeting an Equine Estrogen Catechol Metabolite to the Nucleus","volume":"284","author":"Wang","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/iub.586","article-title":"Mechanism of DNA depurination by carcinogens in relation to cancer initiation","volume":"64","author":"Cavalieri","year":"2012","journal-title":"IUBMB Life"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"12555","DOI":"10.1021\/acscatal.0c02315","article-title":"Demonstrating the Direct Relationship between Hydrogen Evolution Reaction and Catalyst Deactivation in Synthetic Fe Nitrogenases","volume":"10","author":"Benedek","year":"2020","journal-title":"ACS Catal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"10325","DOI":"10.1039\/D1DT01754C","article-title":"Trends in computational molecular catalyst design","volume":"50","author":"Soyemi","year":"2021","journal-title":"Dalt. Trans."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e1354","DOI":"10.1002\/wcms.1354","article-title":"Methods for exploring reaction space in molecular systems","volume":"8","author":"Dewyer","year":"2018","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.1021\/acs.chemrev.8b00361","article-title":"Computational Approach to Molecular Catalysis by 3d Transition Metals: Challenges and Opportunities","volume":"119","author":"Vogiatzis","year":"2019","journal-title":"Chem. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3601","DOI":"10.1021\/cr400388t","article-title":"Quantum Chemical Studies of Mechanisms for Metalloenzymes","volume":"114","author":"Blomberg","year":"2014","journal-title":"Chem. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6430","DOI":"10.1021\/acscatal.0c00983","article-title":"Modeling Enzymatic Enantioselectivity using Quantum Chemical Methodology","volume":"10","author":"Sheng","year":"2020","journal-title":"ACS Catal."},{"key":"ref_32","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Revision C.01, Gaussian, Inc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11623","DOI":"10.1021\/j100096a001","article-title":"Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields","volume":"98","author":"Stephens","year":"1994","journal-title":"J. Phys. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/jcc.540040303","article-title":"Efficient diffuse function-augmented basis sets for anion calculations. III. The 3-21+G basis set for first-row elements, Li-F","volume":"4","author":"Clark","year":"1983","journal-title":"J. Comput. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1002\/jcc.21759","article-title":"Effect of the damping function in dispersion corrected density functional theory","volume":"32","author":"Grimme","year":"2011","journal-title":"J. Comput. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1021\/jp9716997","article-title":"Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model","volume":"102","author":"Barone","year":"1998","journal-title":"J. Phys. Chem. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrm2820","article-title":"Sensors and regulators of intracellular pH","volume":"11","author":"Casey","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1063\/1.1749604","article-title":"The Activated Complex in Chemical Reactions","volume":"3","author":"Eyring","year":"1935","journal-title":"J. Chem. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"An, R., Jia, Y., Wan, B., Zhang, Y., Dong, P., Li, J., and Liang, X. (2014). Non-Enzymatic Depurination of Nucleic Acids: Factors and Mechanisms. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115950"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.steroids.2004.09.011","article-title":"Slow loss of deoxyribose from the N7deoxyguanosine adducts of estradiol-3,4-quinone and hexestrol-3\u2032,4\u2032-quinone","volume":"70","author":"Saeed","year":"2005","journal-title":"Steroids"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1021\/tx050229y","article-title":"The Greater Reactivity of Estradiol-3,4-quinone vs Estradiol-2,3-quinone with DNA in the Formation of Depurinating Adducts: Implications for Tumor-Initiating Activity","volume":"19","author":"Zahid","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6803","DOI":"10.1021\/acscatal.9b01537","article-title":"Scope and Challenge of Computational Methods for Studying Mechanism and Reactivity in Homogeneous Catalysis","volume":"9","author":"Harvey","year":"2019","journal-title":"ACS Catal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1006\/jmbi.1997.1368","article-title":"The entropy cost of protein association","volume":"273","author":"Tamura","year":"1997","journal-title":"J. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1021\/acs.chemrestox.6b00330","article-title":"Combined Docking and Quantum Chemical Study on CYP-Mediated Metabolism of Estrogens in Man","volume":"30","year":"2017","journal-title":"Chem. Res. Toxicol."}],"container-title":["Symmetry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-8994\/13\/9\/1641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:57:30Z","timestamp":1760165850000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-8994\/13\/9\/1641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,6]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["sym13091641"],"URL":"https:\/\/doi.org\/10.3390\/sym13091641","relation":{},"ISSN":["2073-8994"],"issn-type":[{"type":"electronic","value":"2073-8994"}],"subject":[],"published":{"date-parts":[[2021,9,6]]}}}