The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation
Abstract Background Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The purpose of the present study was to uncover whether tamoxifen treatment would act on estrogen met...
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| Format: | Article |
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BMC
2022-05-01
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| Series: | BMC Pharmacology and Toxicology |
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| Online Access: | https://doi.org/10.1186/s40360-022-00574-6 |
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| author | Zhixiang Hao Jiahao Xu Han Zhao Wei Zhou Zhao Liu Shiqing He Xiaoxing Yin Bei Zhang Zhongjian Wang Xueyan Zhou |
| author_facet | Zhixiang Hao Jiahao Xu Han Zhao Wei Zhou Zhao Liu Shiqing He Xiaoxing Yin Bei Zhang Zhongjian Wang Xueyan Zhou |
| author_sort | Zhixiang Hao |
| collection | DOAJ |
| description | Abstract Background Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The purpose of the present study was to uncover whether tamoxifen treatment would act on estrogen metabolism-related biological enzymes and the regulatory effect on estrogen homeostasis to clarify the key factors and potential mechanisms of adverse reactions caused by long-term use of tamoxifen. Method Female SD rats were administrated with tamoxifen CMC-Na solution (p.o.) once daily for four weeks and then housed at room temperature. Serum, breast, liver, uterus, and ovarian tissues were obtained, and the effects of tamoxifen administration on estrogen homeostasis, the expression, and activity of estrogen metabolic enzyme were evaluated. Results Compared with the control group, the estrogen homeostasis was disturbed and the expression and activity of UGT2B1 (homology with human UGT2B7) were significantly reduced in the rats administrated with tamoxifen. The inhibitory effect of tamoxifen on UGT2B7 was dominated by hydrophobic and π-π stacking interactions, resulting in a concentration-dependent inhibition of UGT2B7 activity by tamoxifen and the imbalance of ligand-activated transcription factors, leading to abnormal regulation of UGT2B and disturbance of estrogen homeostasis, which in turn led to adverse reactions of tamoxifen. Conclusion We established links between estrogen metabolism and tamoxifen administration and we proposed that the UGT2B inhibition was involved in the disturbance of estrogen homeostasis and the occurrence of tamoxifen-related adverse reactions. |
| first_indexed | 2024-12-11T16:21:04Z |
| format | Article |
| id | doaj.art-ea0fddbc11c74e34aa435469bd736be0 |
| institution | Directory Open Access Journal |
| issn | 2050-6511 |
| language | English |
| last_indexed | 2024-12-11T16:21:04Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
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| series | BMC Pharmacology and Toxicology |
| spelling | doaj.art-ea0fddbc11c74e34aa435469bd736be02022-12-22T00:58:51ZengBMCBMC Pharmacology and Toxicology2050-65112022-05-0123111310.1186/s40360-022-00574-6The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulationZhixiang Hao0Jiahao Xu1Han Zhao2Wei Zhou3Zhao Liu4Shiqing He5Xiaoxing Yin6Bei Zhang7Zhongjian Wang8Xueyan Zhou9Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityDepartment of Thyroid and Breast Surgery, the Affiliated Hospital of Xuzhou Medical UniversityDepartment of Thyroid and Breast Surgery, the Affiliated Hospital of Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityDepartment of Obstetrics and Gynecology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, College of Pharmacy, Xuzhou Medical UniversityAbstract Background Tamoxifen treatment may induce dysregulation of estrogen homeostasis, leading to the occurrence of related adverse reactions. However, the potential mechanisms are still unclear. The purpose of the present study was to uncover whether tamoxifen treatment would act on estrogen metabolism-related biological enzymes and the regulatory effect on estrogen homeostasis to clarify the key factors and potential mechanisms of adverse reactions caused by long-term use of tamoxifen. Method Female SD rats were administrated with tamoxifen CMC-Na solution (p.o.) once daily for four weeks and then housed at room temperature. Serum, breast, liver, uterus, and ovarian tissues were obtained, and the effects of tamoxifen administration on estrogen homeostasis, the expression, and activity of estrogen metabolic enzyme were evaluated. Results Compared with the control group, the estrogen homeostasis was disturbed and the expression and activity of UGT2B1 (homology with human UGT2B7) were significantly reduced in the rats administrated with tamoxifen. The inhibitory effect of tamoxifen on UGT2B7 was dominated by hydrophobic and π-π stacking interactions, resulting in a concentration-dependent inhibition of UGT2B7 activity by tamoxifen and the imbalance of ligand-activated transcription factors, leading to abnormal regulation of UGT2B and disturbance of estrogen homeostasis, which in turn led to adverse reactions of tamoxifen. Conclusion We established links between estrogen metabolism and tamoxifen administration and we proposed that the UGT2B inhibition was involved in the disturbance of estrogen homeostasis and the occurrence of tamoxifen-related adverse reactions.https://doi.org/10.1186/s40360-022-00574-6Breast cancerTamoxifenEstrogensEstrogen metabolizing enzymeUGT2B |
| spellingShingle | Zhixiang Hao Jiahao Xu Han Zhao Wei Zhou Zhao Liu Shiqing He Xiaoxing Yin Bei Zhang Zhongjian Wang Xueyan Zhou The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation BMC Pharmacology and Toxicology Breast cancer Tamoxifen Estrogens Estrogen metabolizing enzyme UGT2B |
| title | The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| title_full | The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| title_fullStr | The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| title_full_unstemmed | The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| title_short | The inhibition of tamoxifen on UGT2B gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| title_sort | inhibition of tamoxifen on ugt2b gene expression and enzyme activity in rat liver contribute to the estrogen homeostasis dysregulation |
| topic | Breast cancer Tamoxifen Estrogens Estrogen metabolizing enzyme UGT2B |
| url | https://doi.org/10.1186/s40360-022-00574-6 |
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