Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ
UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provid...
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Frontiers Media S.A.
2021-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.628314/full |
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| author | Ya-Di Zhu Xiao-Qing Guan Jing Chen Sheng Peng Moshe Finel Ying-Yuan Zhao Rui-Min Wang Hui-Chang Bi Ming Lei Dan-Dan Wang Guang-Bo Ge |
| author_facet | Ya-Di Zhu Xiao-Qing Guan Jing Chen Sheng Peng Moshe Finel Ying-Yuan Zhao Rui-Min Wang Hui-Chang Bi Ming Lei Dan-Dan Wang Guang-Bo Ge |
| author_sort | Ya-Di Zhu |
| collection | DOAJ |
| description | UDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities. |
| first_indexed | 2024-12-16T18:37:14Z |
| format | Article |
| id | doaj.art-5a19f072ec1e4a7b8c798ddc099ca5f2 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-16T18:37:14Z |
| publishDate | 2021-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-5a19f072ec1e4a7b8c798ddc099ca5f22022-12-21T22:21:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-02-011110.3389/fphar.2020.628314628314Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγYa-Di Zhu0Xiao-Qing Guan1Jing Chen2Sheng Peng3Moshe Finel4Ying-Yuan Zhao5Rui-Min Wang6Hui-Chang Bi7Ming Lei8Dan-Dan Wang9Guang-Bo Ge10Trauma Emergency Center, The Seventh Affiliated People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaTrauma Emergency Center, The Seventh Affiliated People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDivision of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, FinlandSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaSchool of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, ChinaTrauma Emergency Center, The Seventh Affiliated People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaInstitute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaUDP-glucuronosyltransferase 1A1 (UGT1A1) is an essential enzyme in mammals that is responsible for detoxification and metabolic clearance of the endogenous toxin bilirubin and a variety of xenobiotics, including some crucial therapeutic drugs. Discovery of potent and safe UGT1A1 inducers will provide an alternative therapy for ameliorating hyperbilirubinaemia and drug-induced hepatoxicity. This study aims to find efficacious UGT1A1 inducer(s) from natural flavonoids, and to reveal the mechanism involved in up-regulating of this key conjugative enzyme by the flavonoid(s) with strong UGT1A1 induction activity. Among all the tested flavonoids, neobavaisoflavone (NBIF) displayed the most potent UGT1A1 induction activity, while its inductive effects were confirmed by both western blot and glucuronidation activity assays. A panel of nuclear receptor reporter assays demonstrated that NBIF activated PPARα and PPARγ in a dose-dependent manner. Meanwhile, we also found that NBIF could up-regulate the expression of PPARα and PPARγ in hepatic cells, suggesting that the induction of UGT1A1 by NBIF was mainly mediated by PPARs. In silico simulations showed that NBIF could stably bind on pocket II of PPARα and PPARγ. Collectively, our results demonstrated that NBIF is a natural inducer of UGT1A1, while this agent induced UGT1A1 mainly via activating and up-regulating PPARα and PPARγ. These findings suggested that NBIF can be used as a promising lead compound for the development of more efficacious UGT1A1 inducers to treat hyperbilirubinaemia and UGT1A1-associated drug toxicities.https://www.frontiersin.org/articles/10.3389/fphar.2020.628314/fullUDP-glucuronosyltransferase 1A1flavonoidsinductionperoxisome proliferator-activated receptorsneobavaisoflavone |
| spellingShingle | Ya-Di Zhu Xiao-Qing Guan Jing Chen Sheng Peng Moshe Finel Ying-Yuan Zhao Rui-Min Wang Hui-Chang Bi Ming Lei Dan-Dan Wang Guang-Bo Ge Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ Frontiers in Pharmacology UDP-glucuronosyltransferase 1A1 flavonoids induction peroxisome proliferator-activated receptors neobavaisoflavone |
| title | Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ |
| title_full | Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ |
| title_fullStr | Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ |
| title_full_unstemmed | Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ |
| title_short | Neobavaisoflavone Induces Bilirubin Metabolizing Enzyme UGT1A1 via PPARα and PPARγ |
| title_sort | neobavaisoflavone induces bilirubin metabolizing enzyme ugt1a1 via pparα and pparγ |
| topic | UDP-glucuronosyltransferase 1A1 flavonoids induction peroxisome proliferator-activated receptors neobavaisoflavone |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.628314/full |
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