The intracellular mechanism of Berberine-induced inhibition of CYP3A4 activity

Pan-Feng Feng; Long-Xun Zhu; Jing Jie; Peng-Xiang Yang; Xia Chen

doi:10.2174/1381612827666210715155809

The intracellular mechanism of Berberine-induced inhibition of CYP3A4 activity

Pan-Feng Feng, Long-Xun Zhu, Jing Jie, Peng-Xiang Yang, Xia Chen^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

9 Citations (Scopus)

Abstract

Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels.

Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments.

Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway.

Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR.

© 2021 Bentham Science Publishers.

Original language	English
Pages (from-to)	4179-4185
Journal	Current Pharmaceutical Design
Volume	27
Issue number	40
Online published	15 Jul 2021
DOIs	https://doi.org/10.2174/1381612827666210715155809
Publication status	Published - 2021
Externally published	Yes

Funding

This work was supported by Jiangsu Pharmaceutical Association-Hengrui Pharmaceutical Services Special Scientific Research Funding Project (No. H202047), Nantong Science and Technology Plan Project (No. JCZ20169, JC2019146), and Heilongjiang Natural Science Foundation (No. YQ2019H022).

Research Keywords

Berberine
CYP3A4
RT-PCR
Transcription
Ubiquitination degradation
X receptor (PXR)

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abstract = "Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR. {\textcopyright} 2021 Bentham Science Publishers.",

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author = "Pan-Feng Feng and Long-Xun Zhu and Jing Jie and Peng-Xiang Yang and Xia Chen",

year = "2021",

doi = "10.2174/1381612827666210715155809",

language = "English",

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T1 - The intracellular mechanism of Berberine-induced inhibition of CYP3A4 activity

AU - Feng, Pan-Feng

AU - Zhu, Long-Xun

AU - Jie, Jing

AU - Yang, Peng-Xiang

AU - Chen, Xia

PY - 2021

Y1 - 2021

N2 - Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR. © 2021 Bentham Science Publishers.

AB - Background: Berberine (BBR) is an isoquinoline alkaloid extracted from the Chinese medicine, exerting a variety of pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some reports indicated that BBR could inhibit the activity of CYP3A4. However, the underlying mechanisms are not completely understood. CYP3A4 is reported to be transcriptionally regulated by two nuclear receptors, nuclear transcription X receptor (PXR) and constitutive androstane receptor (CAR), and degraded via the ubiquitin-proteasome system. Hence, we tried to explore the mechanisms of CYP3A4 inhibition on both transcriptive and protein levels. Methods: Western Blot, RT-PCR and Co-immunoprecipitation were used to perform the experiments. Results: Our results showed that BBR inhibited the transcription of CYP3A4 gene by downregulating PXR. In addition, BBR accelerated the degradation of CYP3A4 protein via polyubiquitination pathway. Conclusion: These findings may lead to the determination of novel drug-drug interactions with BBR, and contribute to future clinical application of BBR. © 2021 Bentham Science Publishers.

KW - Berberine

KW - CYP3A4

KW - RT-PCR

KW - Transcription

KW - Ubiquitination degradation

KW - X receptor (PXR)

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The intracellular mechanism of Berberine-induced inhibition of CYP3A4 activity

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