Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components
Abstract
The concurrent use of herbal medicinals with prescription and over-the-counter drugs carries a risk for unanticipated adverse drug-botanical pharmacokinetic interactions, particularly as a result of cytochrome P450 (P450) inhibition. Extracts of goldenseal (Hydrastis canadensis) containing approximately equal concentrations ( approximately 17 mM) of two methylenedioxyphenyl alkaloids, berberine and hydrastine, inhibited with increasing potency (CYP2C9) diclofenac 4'-hydroxylation, (CYP2D6) bufuralol 1'-hydroxylation, and (CYP3A4) testosterone 6beta-hydroxylation activities in human hepatic microsomes. The inhibition of testosterone 6beta-hydroxylation activity was noncompetitive with an apparent Ki of 0.11% extract. Of the methylenedioxyphenyl alkaloids, berberine (IC50 = 45 microM) was the more inhibitory toward bufuralol 1'-hydroxylation and hydrastine (IC50 approximately 350 microM for both isomers), toward diclofenac 4'-hydroxylation. For testosterone 6beta-hydroxylation, berberine was the least inhibitory component (IC50 approximately 400 microM). Hydrastine inhibited testosterone 6beta-hydroxylation with IC50 values for the (+)- and (-)-isomers of 25 and 30 microM, respectively. For (-)-hydrastine, an apparent Ki value of 18 microM without preincubation and an NADPH-dependent mechanism-based inhibition with a kinactivation of 0.23 min(-1) and a KI of approximately 110 microM were determined. Cytochrome P450 metabolic-intermediate (MI) complex formation could be demonstrated for both hydrastine isomers. With expressed P450 isoforms, hydrastine formed a P450 MI complex with CYP2C9, CYP2D6, and CYP3A4. Coexpression of cytochrome b5 with the P450 isoforms enhanced the rate but not the extent of P450 MI complex formation.
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(−)-β-hydrastine appears to be the main alkaloid responsible for time-dependent CYP3A inhibition, and berberine is a weaker CYP3A4 inhibitor.
“In fact, (−)-β-hydrastine appears to be the main alkaloid responsible for this time-dependent inhibition, berberine being a weaker CYP3A4 inhibitor; therefore, the alkaloid profile and botanical identity of the product influence the magnitude of the interaction [71,74].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [74]
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“…(sirolimus); tacrolimus by extrapolation, PBPK-supported [63,81] Midazolam (CYP3A probe) CYP3A4 inhibition (goldenseal) [72,73] ↑ AUC ≈ 40–60% [73,74] B—clinical probe-substrate study (goldenseal) [72,73] Metformin OCT1/OCT2/MATE1inhibition[65,82] Bidirectional PK effect ( ↓ Cmax/AUC, ↑ renal…”
- Authors
- Chatterjee, P., & Franklin, M. R.
- Affiliations
- University of Utah (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 31
- Issue
- 11
- Pages
- 1391-1397
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2134981275
- Cited by
- 146
- References
- 22
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 5 · 2016: 3 · 2015: 11 · 2014: 8 · 2013: 4 · 2012: 15
- FWCI
- 5.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Complementary and alternative medicine › Complementary and Alternative Medicine Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- goldenseal, Hydrastis canadensis, berberine, hydrastine, cytochrome P450 inhibition, CYP2C9, CYP2D6, CYP3A4, mechanism-based inhibition, testosterone 6beta-hydroxylation, cytochrome b5, herbal medicine
- MeSH terms
- Cytochrome P-450 Enzyme System, Dioxoles, Dose-Response Relationship, Drug, Humans, Hydrocarbons, Isoenzymes, Methane, Microsomes, Liver, Plant Extracts, Plant Roots, Hydrastis, Cytochrome P-450 Enzyme Inhibitors
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