Bioactivities of berberine metabolites after transformation through CYP450 isoenzymes
Open accessAbstract
BACKGROUND: Berberine (BBR) is a drug with multiple effects on cellular energy metabolism. The present study explored answers to the question of which CYP450 (Cytochrome P450) isoenzymes execute the phase-I transformation for BBR, and what are the bioactivities of its metabolites on energy pathways. METHODS: BBR metabolites were detected using LC-MS/MS. Computer-assistant docking technology as well as bioassays with recombinant CYP450s were employed to identify CYP450 isoenzymes responsible for BBR phase-I transformation. Bioactivities of BBR metabolites in liver cells were examined with real time RT-PCR and kinase phosphorylation assay. RESULTS: In rat experiments, 4 major metabolites of BBR, berberrubine (M1), thalifendine (M2), demethyleneberberine (M3) and jatrorrhizine (M4) were identified in rat's livers using LC-MS/MS (liquid chromatography-tandem mass spectrometry). In the cell-free transformation reactions, M2 and M3 were detectable after incubating BBR with rCYP450s or human liver microsomes; however, M1 and M4 were below detective level. CYP2D6 and CYP1A2 played a major role in transforming BBR into M2; CYP2D6, CYP1A2 and CYP3A4 were for M3 production. The hepatocyte culture showed that BBR was active in enhancing the expression of insulin receptor (InsR) and low-density-lipoprotein receptor (LDLR) mRNA, as well as in activating AMP-activated protein kinase (AMPK). BBR's metabolites, M1-M4, remained to be active in up-regulating InsR expression with a potency reduced by 50-70%; LDLR mRNA was increased only by M1 or M2 (but not M3 and M4) with an activity level 35% or 26% of that of BBR, respectively. Similarly, AMPK-α phosphorylation was enhanced by M1 and M2 only, with a degree less than that of BBR. CONCLUSIONS: Four major BBR metabolites (M1-M4) were identified after phase-I transformation in rat liver. Cell-free reactions showed that CYP2D6, CYP1A2 and CYP3A4 seemed to be the dominant CYP450 isoenzymes transforming BBR into its metabolites M2 and M3. BBR's metabolites remained to be active on BBR's targets (InsR, LDLR, and AMPK) but with reduced potency.
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Berberine and its metabolites are themselves substrates and/or inhibitors of several enzymes and transporters, broadening the spectrum of interactions.
“Berberine and its metabolites (berberrubine, thalifendine, demethyleneberberine, and jatrorrhizine), formed predominantly by CYP1A2, CYP2D6 and CYP3A4, are themselves substrates and/or inhibitors of several enzymes and transporters, which broadens the spectrum of interactions [59,60,61].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [61]
The Results and Discussion section reports that CYP1A2, CYP2D6 and CYP3A4 transform berberine, supporting its role as a substrate of several enzymes. The paper does not establish that berberine or its metabolites inhibit those enzymes or are substrates or inhibitors of transporters; the CYP inhibitors in its assays were other compounds. It therefore does not support the claimed broader spectrum of interactions. (LLM, conf=0.88)
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References 36 · Cited by 109
Research works printed but not linked: 1
- Zhao GP Zhao GP Huanglian Chinese Materia Medica Dictionary 2006 2 2 Shanghai: Science and Technology Press 2815 2820
- Authors
- Li, Y., Ren, G., Wang, Y.-X., Kong, W.-J., Yang, P., Wang, Y.-M., Li, Y.-H., Yi, H., Li, Z.-R., Song, D.-Q., & Jiang, J.-D.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Jiang, Jian-Dong
- Venue
- Journal of Translational Medicine
- Published
- 2011-05-15
- Volume
- 9
- Issue
- 1
- Pages
- 62-62
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC3103436
- OpenAlex
- W2117891931
- Cited by
- 109
- References
- 36
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 7 · 2023: 12 · 2022: 13 · 2021: 8 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 6 · 2016: 6 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 6
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (90913002)
- Topics
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- berberine, phase I metabolism, berberrubine, jatrorrhizine, CYP2D6, CYP1A2, CYP3A4, AMPK, insulin receptor, LDL receptor, energy metabolism
- MeSH terms
- Animals, Berberine, Biotransformation, Cytochrome P-450 Enzyme System, Humans, Isoenzymes, Liver, Male, Receptor, Insulin, Receptors, LDL, Rats, Wistar, Metabolic Detoxication, Phase I, Rats, AMP-Activated Protein Kinases, Hep G2 Cells
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