ArticleActa pharmacologica Sinica2019
Different structures of berberine and five other protoberberine alkaloids that affect P-glycoprotein-mediated efflux capacity.
Article in Acta pharmacologica Sinica, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 48 citations in OpenAlex.
- Discovery of natural RORγt inhibitor using machine learning, virtual screening, and in vivo validation.Journal of advanced research · 2026Article
- Berberine as a Multifunctional Adjuvant in Cancer Therapy: Mechanistic Insights, Nanotechnological Strategies, and Translational Challenges.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Therapeutic Potential of Qilianxiaopi Formula: Targeting ADAM17-Mediated Chronic Inflammation in Atrophic Gastritis.Pharmaceuticals (Basel, Switzerland) · 2025Article
- Natural metabolites used in traditional Chinese medicine for cardiovascular diseases: pharmacological mechanisms, evidence, and future directions.Frontiers in pharmacology · 2025Review
- Development of Traditional Chinese Medicine in combination with EGFR Inhibitors against Cancer.Journal of Cancer · 2025Review
- Exploring the Therapeutic Potentials and Molecular Mechanisms ofPreventive nutrition and food science · 2024Article
- Modulation of Multidrug Resistance Transporters by Food Components and Dietary Supplements: Implications for Cancer Therapy Efficacy and Safety.Current issues in molecular biology · 2024Review
- Differences in Metabolite Profiles of Dihydroberberine and Micellar Berberine in Caco-2 Cells and Humans-A Pilot Study.International journal of molecular sciences · 2024Article
- Recent Applications of Protoberberines as Privileged Starting Materials for the Development of Novel Broad-Spectrum Antiviral Agents: A Concise Review (2017-2023).ACS pharmacology & translational science · 2024Review
- Neuroprotective effect and preparation methods of berberine.Frontiers in pharmacology · 2024Review
- Effect of Oregon grape root extracts on P-glycoprotein mediated transport inJournal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2023Article
- Berberine-containing natural-medicine with boiled peanut-OIT induces sustained peanut-tolerance associated with distinct microbiota signature.Frontiers in immunology · 2023Article
- Berberine-microbiota interplay: orchestrating gut health through modulation of the gut microbiota and metabolic transformation into bioactive metabolites.Frontiers in pharmacology · 2023Article
- Isoquinoline Alkaloids fromInternational journal of molecular sciences · 2022Article
- Research progress on the pharmacological effects of berberine targeting mitochondria.Frontiers in endocrinology · 2022Review
- Diversity in Chemical Structures and Biological Properties of Plant Alkaloids.Molecules (Basel, Switzerland) · 2021Review
- Co-Delivery of Berberine Chloride and Tariquidar in Nanoliposomes Enhanced Intracellular Berberine Chloride in a Doxorubicin-Resistant K562 Cell Line Due to P-gp Overexpression.Pharmaceutics · 2021Article
- Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment.Evidence-based complementary and alternative medicine : eCAM · 2021Review
- Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization.Molecules (Basel, Switzerland) · 2020Review
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Authors and funding
9 authors at 3 institutions in 1 country.
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Abstract
Berberine, berberrubine, thalifendine, demethyleneberberine, jatrorrhizine, and columbamine are six natural protoberberine alkaloid (PA) compounds that display extensive pharmacological properties and share the same protoberberine molecular skeleton with only slight substitution differences. The oral delivery of most PAs is hindered by their poor bioavailability, which is largely caused by P-glycoprotein (P-gp)-mediated drug efflux. Meanwhile, P-gp undergoes large-scale conformational changes (from an inward-facing to an outward-facing state) when transporting substrates, and these changes might strongly affect the P-gp-binding specificity. To confirm whether these six compounds are substrates of P-gp, to investigate the differences in efflux capacity caused by their trivial structural differences and to reveal the key to increasing their binding affinity to P-gp, we conducted a series of in vivo, in vitro, and in silico assays. Here, we first confirmed that all six compounds were substrates of P-gp by comparing the drug concentrations in wild-type and P-gp-knockout mice in vivo. The efflux capacity (net efflux) ranked as berberrubine > berberine > columbamine ~ jatrorrhizine > thalifendine > demethyleneberberine based on in vitro transport studies in Caco-2 monolayers. Using molecular dynamics simulation and molecular docking techniques, we determined the transport pathways of the six compounds and their binding affinities to P-gp. The results suggested that at the early binding stage, different hydrophobic and electrostatic interactions collectively differentiate the binding affinities of the compounds to P-gp, whereas electrostatic interactions are the main determinant at the late release stage. In addition to hydrophobic interactions, hydrogen bonds play an important role in discriminating the binding affinities.
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