Berberine and berberrubine promote the expression of CYP3A4 via enhancing the binding of nuclear receptor PXR
Open accessAbstract
BACKGROUND: Berberine is currently co-administered with statins in clinical practice for hyperlipidemia management. This study aimed to investigate the effects of berberine and berberrubine on CYP3A4 expression and the regulatory mechanism. METHODS: Using rifampicin as a positive control group, HepG2 cells were treated with different concentrations of berberine and berberrubine. Q-PCR was employed to detect the expression levels of CYP3A4 mRNA in response to the drugs, and Western blot was utilized to determine the expression of CYP3A4 and PXR proteins. Dual luciferase reporter gene assay and RNA interference technology were used to silence PXR to explore the mechanism of berberine and berberrubine regulation of CYP3A4. RESULTS: Compared with the blank control group, both berberine and berberrubine could induce CYP3A4 mRNA expression in a concentration-dependent manner (P < 0.05). After treatment with 50 µM berberine and 60 µM berbamine for 48 h, the expression of CYP3A4 in HepG 2 cells was increased by 2.5 and 2.7 times, respectively. Berberine (10 ~ 50 µM) and berberrubine (15 ~ 60 µM) could upregulate the expression of PXR nuclear protein in a dose-dependent manner. Berberine and berbamine at different concentrations significantly upregulated the activity of the dual luciferase constructed based on PXR (P < 0.05), while silencing PXR reduced the inductive effects of berberine and berbamine on CYP3A4. Berberine and berbamine at different concentrations significantly upregulated the activity of the dual luciferase constructed based on PXR (P < 0.05), while silencing PXR reduced the inductive effects of berberine and berbamine on CYP3A4. CONCLUSION: Berberine and berberrubine can promote the expression of CYP3A4 protein in HepG2 cells by inducing the nuclear receptor PXR to bind to the promoter of CYP3A4.
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Berberine and berberrubine activate PXR at micromolar concentrations in vitro, the same range as the enzyme-inhibition IC50 values and three to four orders of magnitude above plasma concentrations.
“Berberine and berberrubine activate PXR at micromolar concentrations in the in vitro systems used, the same range as the enzyme-inhibition IC50 values reported above and three to four orders of magnitude above the plasma concentrations set out in Section 2.1 [75].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [75]
The Discussion reports PXR-related reporter activity at 10–50 µM berberine and 15–60 µM berberrubine, and gives much lower plasma concentrations. It mentions enzyme inhibition but provides no inhibition IC50 values, so this source cannot establish that the activation concentrations are in the same range as those values. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe coexistence of inhibition and possible transcriptional induction means the net direction of the effect on a CYP3A4 victim may depend on dose, duration of exposure, and tissue.
“The coexistence of inhibition, acute and, for CYP2D6, quasi-irreversible, with possible transcriptional induction upon chronic administration explains why the net direction of the effect on a CYP3A4 victim may depend on dose, duration of exposure, and tissue; this phenomenon calls for caution in the linear extrapolation of in vitro inhibition data to the clinical situation [75].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [75]
The Discussion says berberine may both inhibit CYP3A4 activity in vitro and induce its expression in HepG2 cells; it leaves the net effect on CYP3A4 substrates, especially after long-term use, unresolved. The Results report dose-dependent induction, but the paper does not establish that the net effect varies by tissue or measure how dose changes that net effect. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe contribution of quasi-irreversible CYP2D6 inhibition, the balance between CYP3A4 inhibition and PXR-mediated induction, the concentration-response relationship for that induction and the time at which it begins, and the duration of both effects after berberine is stopped all need to be quantified in humans; at present each is extrapolated from in vitro systems.
“The contribution of quasi-irreversible CYP2D6 inhibition, the balance between CYP3A4 inhibition and PXR-mediated induction, the concentration–response relationship for that induction and the time at which it begins, and the duration of both effects after berberine is stopped, all need to be quantified in humans; at present each is extrapolated from in vitro systems [59,75].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [75]
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Experimental — accuracy not yet measuredBerberine transcriptionally induces CYP3A4.
“transcriptional induction, of CYP3A4”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [75]
Berberine and its metabolite berberrubine can induce, in a concentration-dependent manner, the expression of CYP3A4 through activation of the nuclear pregnane X receptor (PXR).
“Recent data show that berberine and its metabolite berberrubine can induce, in a concentration-dependent manner, the expression of CYP3A4 through activation of the nuclear pregnane X receptor (PXR) [75].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [75]
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“…transcriptional induction upon chronic administration explains why the net direction of the effect on a CYP3A4 victim may depend on dose, duration of exposure, and tissue; this phenomenon calls for caution in the linear extrapolation of in vitro inhibition data to the clinical situation [75].”
InfluentialWang, J., Jing, C., Han, Y., Zhu, Z., Yang, M., Zhuang, X., Zhou, K., Liu, J., & Li, L. (2026) · Journal of Pharmacy and Pharmacology · doi:10.1093/jpp/rgag118
- Authors
- Xiao, G.-M., Lu, T., Zhu, D., & Liu, M.-Y.
- Affiliations
- Ganzhou People's Hospital (CN)
- Gannan Medical University (CN)
- Nanchang University (CN)
- ORCID
- Zhu, Dandan
- Venue
- BMC Pharmacology and Toxicology
- Published
- 2025-11-06
- Volume
- 26
- Issue
- 1
- Pages
- 187-187
- ISSN
- 2050-6511 (ISSN-L)
- PMC
- PMC12593850
- OpenAlex
- W4415964329
- Cited by
- 2
- References
- 18
- Citations by year
- 2026: 2
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- BMC Pharmacology and Toxicology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Health Commission of Jiangxi Province
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- berberine, berberrubine, berbamine, CYP3A4, pregnane X receptor, drug-induced liver injury, drug-drug interactions, CYP3A4 induction, transcriptional regulation, HepG2 cells
- MeSH terms
- Pregnane X Receptor, Berberine, Humans, Receptors, Steroid, RNA, Messenger, Benzylisoquinolines, Cytochrome P-450 CYP3A, Hep G2 Cells
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