Modulation of CYP3A4 and CYP2C9 activity by Bulbine natalensis and its constituents: An assessment of HDI risk of B. natalensis containing supplements

Phytomedicine. 2021 Jan:81:153416. doi: 10.1016/j.phymed.2020.153416. Epub 2020 Nov 19.

Abstract

Background: Bulbine natalensis is an African-folk medicinal plant used as a dietary supplement for enhancing sexual function and muscle strength in males by presumably boosting testosterone levels, but no scientific information is available about the possible herb-drug interaction (HDI) risk when bulbine-containing supplements are concomitantly taken with prescription drugs.

Purpose: This study was aimed to investigate the HDI potential of B. natalensis in terms of the pregnane X receptor (PXR)-mediated induction of major drug-metabolizing cytochrome P450 enzyme isoforms (i.e., CYP3A4 and CYP2C9) as well as inhibition of their catalytic activity.

Results: We found that a methanolic extract of B. natalensis activated PXR (EC50 6.2 ± 0.6 µg/ml) in HepG2 cells resulting in increased mRNA expression of CYP3A4 (2.40 ± 0.01 fold) and CYP2C9 (3.37 ± 0.3 fold) at 30 µg/ml which was reflected in increased activites of the two enzymes. Among the constituents of B. natalensis, knipholone was the most potent PXR activator (EC50 0.3 ± 0.1 µM) followed by bulbine-knipholone (EC50 2.0 ± 0.5 µM), and 6'-methylknipholone (EC50 4.0 ± 0.5 µM). Knipholone was also the most effective in increasing the expression of CYP3A4 (8.47 ± 2.5 fold) and CYP2C9 (2.64 ± 0.3 fold) at 10 µM. Docking studies further confirmed the unique structural features associated with knipholones for their superior inductive potentials in the activation of PXR compared to other anthraquinones. In a CYP inhibition assay, the methanolic extract as well as the anthraquinones strongly inhibited the catalytic activity of CYP2C9 while, inhibition of CYP3A4 was weak.

Conclusions: These results suggest that consumption of B. natalensis may pose a potential risk for HDI if taken with conventional medications that are substrates of CYP3A4 and CYP2C9 and may contribute to unanticipated adverse reactions or therapeutic failures. Further studies are warranted to validate these findings and establish their clinical relevancy.

Keywords: Bulbine natalensis; Cytochrome P450; Herb-drug interactions; Knipholone; Pregnane X receptor.

MeSH terms

  • Asphodelaceae / chemistry*
  • Cytochrome P-450 CYP2C9 / metabolism*
  • Cytochrome P-450 CYP2C9 Inhibitors / chemistry
  • Cytochrome P-450 CYP2C9 Inhibitors / pharmacology
  • Cytochrome P-450 CYP3A / metabolism*
  • Cytochrome P-450 CYP3A Inhibitors / chemistry
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Dietary Supplements* / adverse effects
  • Hep G2 Cells
  • Herb-Drug Interactions*
  • Humans
  • Male
  • Molecular Docking Simulation
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Plants, Medicinal / chemistry
  • Pregnane X Receptor / chemistry
  • Pregnane X Receptor / genetics
  • Pregnane X Receptor / metabolism

Substances

  • Cytochrome P-450 CYP2C9 Inhibitors
  • Cytochrome P-450 CYP3A Inhibitors
  • NR1I2 protein, human
  • Plant Extracts
  • Pregnane X Receptor
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human