Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy
Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE<sub>2</sub&...
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doaj-1a783dac1fdb44cc8b611f656e0765a62021-07-15T15:38:33ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-01227222722210.3390/ijms22137222Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement TherapyYoshinori Okamoto0Hideto Jinno1Shinji Itoh2Shinya Shibutani3Faculty of Pharmacy, Meijo University, Nagoya 468-8503, JapanFaculty of Pharmacy, Meijo University, Nagoya 468-8503, JapanFaculty of Pharmaceutical Sciences, Hokkaido University of Science, Sapporo 006-8585, JapanDepartment of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USAHuman estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE<sub>2</sub>) or 4-chloro-17β-estradiol (4-ClE<sub>2</sub>) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E<sub>2</sub>) frequently induced mammary tumors while both 2-ClE<sub>2</sub> and 4-ClE<sub>2</sub> did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE<sub>2</sub>) nor 4-chloro-17α-ethinylestradiol (4-ClEE<sub>2</sub>) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E<sub>2</sub> may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE<sub>2</sub> and 4-ClE<sub>2</sub> administered subcutaneously and 2-ClEE<sub>2</sub> and 4-ClEE<sub>2</sub> given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E<sub>2</sub>. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT.https://www.mdpi.com/1422-0067/22/13/7222estrogenchlorinationmammary tumoruterotrophic activityhormone replacement therapyDNA damage |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yoshinori Okamoto Hideto Jinno Shinji Itoh Shinya Shibutani |
spellingShingle |
Yoshinori Okamoto Hideto Jinno Shinji Itoh Shinya Shibutani Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy International Journal of Molecular Sciences estrogen chlorination mammary tumor uterotrophic activity hormone replacement therapy DNA damage |
author_facet |
Yoshinori Okamoto Hideto Jinno Shinji Itoh Shinya Shibutani |
author_sort |
Yoshinori Okamoto |
title |
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy |
title_short |
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy |
title_full |
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy |
title_fullStr |
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy |
title_full_unstemmed |
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy |
title_sort |
less carcinogenic chlorinated estrogens applicable to hormone replacement therapy |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-07-01 |
description |
Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE<sub>2</sub>) or 4-chloro-17β-estradiol (4-ClE<sub>2</sub>) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E<sub>2</sub>) frequently induced mammary tumors while both 2-ClE<sub>2</sub> and 4-ClE<sub>2</sub> did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE<sub>2</sub>) nor 4-chloro-17α-ethinylestradiol (4-ClEE<sub>2</sub>) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E<sub>2</sub> may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE<sub>2</sub> and 4-ClE<sub>2</sub> administered subcutaneously and 2-ClEE<sub>2</sub> and 4-ClEE<sub>2</sub> given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E<sub>2</sub>. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT. |
topic |
estrogen chlorination mammary tumor uterotrophic activity hormone replacement therapy DNA damage |
url |
https://www.mdpi.com/1422-0067/22/13/7222 |
work_keys_str_mv |
AT yoshinoriokamoto lesscarcinogenicchlorinatedestrogensapplicabletohormonereplacementtherapy AT hidetojinno lesscarcinogenicchlorinatedestrogensapplicabletohormonereplacementtherapy AT shinjiitoh lesscarcinogenicchlorinatedestrogensapplicabletohormonereplacementtherapy AT shinyashibutani lesscarcinogenicchlorinatedestrogensapplicabletohormonereplacementtherapy |
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