Bulbine natalensis (currently Bulbine latifolia) and select bulbine knipholones modulate the activity of AhR, CYP1A2, CYP2B6, and P-gp

Abstract

Bulbine natalensis, an emerging medicinal herb on the global market with androgenic properties, is often formulated in dietary supplements that promote perceived sexual enhancement. However, to date, comprehensive safety studies of B. natalensis are lacking, particularly those related to its herb-drug interaction potential. The purpose of this study was to assess the inductive and inhibitory effects of extracts and pure compounds of B. natalensis on human cytochrome P-450 isozymes in vitro. Our findings demonstrated that both water and methanolic extracts of B. natalensis as well as knipholone, bulbine-knipholone, and 6′-O-methylknipholone dose-dependently increased mRNA expression encoded by CYP2B6, CYP1A2, and ABCB1 genes. Functional analyses showed that water (60 to 2.20 µg/mL) and methanolic (30 to 3.75 µg/mL) extracts and knipholones (10 to 0.33 µM) increased CYP2B6 and CYP1A2 activity in a dose-dependent manner. Additionally, water extract (60 µg/mL), methanolic extract (30 µg/mL), and knipholone (10 µM) caused activation of the aryl hydrocarbon receptor up to 11.1 ± 0.7, 8.9 ± 0.6, and 7.1 ± 2.0-fold, respectively. Furthermore, inhibition studies revealed that methanolic extract attenuated the activity of metabolically active CYP1A2 (IC50, 22.6 ± 0.4 µg/mL) and CYP2B6 (IC50, 34.2 ± 6.6 µg/mL) proteins, whereas water extracts had no inhibitory effect on either isoform. These findings suggest that chronic consumption of B. natalensis may affect normal homeostasis of select CYPs with subsequent risks for HDIs when concomitantly ingested with conventional medications that are substrates of CYP2B6 and CYP1A2. However, more in-depth translational studies are required to validate our current findings and their clinical relevance.

A review on phytochemicals, pharmacological activities, drug interactions, and associated toxicities of licorice (Glycyrrhizasp.)

“…Several recent studies have shown that dietary phytochemicals can exhibit dual-functional behaviors: (1) They may act as catalytic inhibitors for posttranslationally matured proteins like CYPs and Pgp. (2) They may also function as agonists for nuclear receptors (like CAR, PXR, and AhR) and increase the expression of metabolically active CYPs proteins (Fantoukh et al, 2019;Husain et al, 2021a;Husain et al, 2021b). Licorice significantly inhibited the activity of translationally matured CYPs as evident by the above-mentioned literature.…”

Lysiphyllum strychnifolium (Craib) A. Schmitz Extracts Moderate the Expression of Drug-Metabolizing Enzymes: In Vivo Study to Clinical Propose

“…The most regular mechanisms of herb extracts imply the induction or inhibition of CYP450 expression, which correlates with protein synthesis [ 34 ] and enzyme activity [ 2 ]. The stimulation of CYP450 enzymes enhances drug clearance, leading to a decrease in the therapeutic effect, while inhibition results in a decrease in drug excretion and increases the drug plasma concentration, causing toxicity and therapeutic failure [ 2 , 15 ]. In this study, we reported the Que and GA derived from LS-SE and LS-LW.…”

“…HDIs mostly depend on the effects of CYP450 and drug transporters, i.e., p-glycoprotein (p-gp). The expression of CYPs450 and p-gp is regulated by various transcription factors, such as nuclear receptors such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), or basic helix-loop-helix/Per-Arnt-Sim such as AhR, which are activated by specific endogenous or exogenous ligands [ 15 ]. HDIs occur in the liver and in the gastrointestinal epithelium due to the presence of CYP450 enzymes [ 16 ].…”

In Vitro Metabolism and CYP-Modulating Activity of Lavender Oil and Its Major Constituents

“…A human AhR reporter assay systems (INDIGO Biosciences, State College, PA, USA) was used for determining the activation of AhR. The assay was performed according to the instructions provided by the supplier and the detailed procedure has been described earlier [ 27 ]. Briefly, a 200 µL suspension of reporter cells was added to the wells of a 96-well plate.…”