Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents

Haron, Mona H.; Avula, Bharathi; Ali, Zulfiqar; Chittiboyina, Amar G.; Khan, Ikhlas A.; Li, Jing; Wang, Vivian; Wu, Chao‐Liang; Khan, Shabana I.

doi:10.1080/19390211.2022.2050875

Cited by 8 publications

(11 citation statements)

References 46 publications

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“…ethanol extracts and pure compounds of five Glycyrrhiza species were evaluated for their effects on major CYP isoforms, which are regulated by PXR (3A4 and 1A2). 41 The study revealed that glycycoumarin showed the highest induction (3-fold) of CYP3A4 enzymatic activity at 30 μM followed by licoisoflavone A with >2-fold induction. It is worth noting that glabridin did not induce CYP3A4 enzymatic activity despite its high PXR activation.…”

Section: Resultsmentioning

confidence: 91%

“…No significant increase in 3A4 enzymatic levels was noticed, even though at least 6-fold PXR activation was observed with glabridin. 41 On the contrary, 2,4-dihydroxyphenyl group on the glabridin scaffold were critical for CYP450 interactions and its antioxidant properties. 42 , 43 Moreover, glabridin was identified to inactivate the enzymatic activities of 3A4, 2B6, 44 and other isozymes and transporters using a UHPLC–MS/MS cocktail assay 45 and serve as a competitive inhibitor of CYP2E1 isozyme.…”

Section: Resultsmentioning

confidence: 99%

“…In order to gauge the overall modulatory effects on PXR, aq. ethanol extracts and pure compounds of five Glycyrrhiza species were evaluated for their effects on major CYP isoforms, which are regulated by PXR (3A4 and 1A2) . The study revealed that glycycoumarin showed the highest induction (3-fold) of CYP3A4 enzymatic activity at 30 μM followed by licoisoflavone A with >2-fold induction.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, licoisoflavone A did not induce CYP1A2 enzymatic activity at any tested concentration. Furthermore, selected extracts and marker compounds including glycycoumarin were also evaluated for their effects on the metabolism of two antiretroviral drugs, rilpivirine and dolutegravir, in hepatocytes …”

Section: Resultsmentioning

confidence: 99%

“…The preparation of licorice root extracts were achieved as described by Haron et al The pure compounds, glabridin, isoliquiritigenin, licoisoflavone A, liquiritin, licoisoflavanone, and glycycoumarin were obtained from the methanol extract of botanically verified licorice by column chromatography over normal silica gel, reversed-phase silica (RP-18), and Sephadex LH-20, as well as preparative thin-layer chromatography (PTLC) . Product integrity and purity of all six flavonoids were characterized using NMR, high-resolution mass spectrometry, and HPLC. , Isoliquiritigenin, glabridin, and glycycoumarin were identified with >95% purity. Whereas, liquritin, licoisoflavonone, and licoisoflavone A were identified with >90% purity.…”

Section: Methodsmentioning

confidence: 99%

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Computational Tools to Expedite the Identification of Potential PXR Modulators in Complex Natural Product Mixtures: A Case Study with Five Closely Related Licorice Species

et al. 2022

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The genus Glycyrrhiza , comprising approximately 36 spp., possesses complex structural diversity and is documented to possess a wide spectrum of biological activities. Understanding and finding the mechanisms of efficacy or safety for a plant-based therapy is very challenging, yet it is crucial and necessary to understand the polypharmacology of traditional medicines. Licorice extract was shown to modulate the xenobiotic receptors, which might manifest as a potential route for natural product-induced drug interactions. However, different mechanisms could be involved in this phenomenon. Since the induced herb–drug interaction of licorice supplements via Pregnane X receptor (PXR) is understudied, we ventured out to analyze the potential modulators of PXR in complex mixtures such as whole extracts by applying computational mining tools. A total of 518 structures from five species of Glycyrrhiza : 183 ( G. glabra ), 180 ( G. uralensis ), 100 ( G. inflata ), 33 ( G. echinata ), and 22 ( G. lepidota ) were collected and post-processed to yield 387 unique compounds. Visual inspection of top candidates with favorable ligand–PXR interactions and the highest docking scores were identified. The in vitro testing revealed that glabridin (GG-14) is the most potent PXR activator among the tested compounds, followed by licoisoflavone A, licoisoflavanone, and glycycoumarin. A 200 ns molecular dynamics study with glabridin confirmed the stability of the glabridin-PXR complex, highlighting the importance of computational methods for rapid dereplication of potential xenobiotic modulators in a complex mixture instead of undertaking time-consuming classical biological testing of all compounds in a given botanical.

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Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Computational Tools to Expedite the Identification of Potential PXR Modulators in Complex Natural Product Mixtures: A Case Study with Five Closely Related Licorice Species

et al. 2022

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The acute toxic effect of Chinese medicine Fuzi is exacerbated in kidney yang deficiency mice due to metabolic difference

Jiang,

Li,

Fan

et al. 2024

Journal of Ethnopharmacology

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Evaluation of the Herb–Drug Interaction (HDI) Potential of Zingiber officinale and Its Major Phytoconstituents

Husain

Dale

Idrisi

et al. 2023

J. Agric. Food Chem.

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Ginger is currently one of the most popular herbs commonly added to diverse foods, beverages, and dietary supplements. We evaluated the ability of a well-characterized ginger extract, and several of its phytoconstituents, to activate select nuclear receptors as well as modulate the activity of various cytochrome P450s and ATP-binding cassette (ABC) transporters because phytochemical-mediated modulation of these proteins underlies many clinically relevant herb–drug interactions (HDI). Our results revealed ginger extract activated the aryl hydrocarbon receptor (AhR) in AhR-reporter cells and pregnane X receptor (PXR) in intestinal and hepatic cells. Among the phytochemicals investigated, (S)-6-gingerol, dehydro-6-gingerdione, and (6S,8S)-6-gingerdiol activated AhR, while 6-shogaol, 6-paradol, and dehydro-6-gingerdione activated PXR. Enzyme assays showed that ginger extract and its phytochemicals dramatically inhibited the catalytic activity of CYP3A4, 2C9, 1A2, and 2B6, and efflux transport capabilities of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dissolution studies with ginger extract conducted in biorelevant simulated intestinal fluid yielded (S)-6-gingerol and 6-shogaol concentrations that could conceivably exceed cytochrome P450 (CYP) IC50 values when consumed in recommended doses. In summary, overconsumption of ginger may disturb the normal homeostasis of CYPs and ABC transporters, which in turn, may elevate the risk for HDIs when consumed concomitantly with conventional medications.

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Assessment of Herb-Drug Interaction Potential of Five Common Species of Licorice and Their Phytochemical Constituents

Cited by 8 publications

References 46 publications

Computational Tools to Expedite the Identification of Potential PXR Modulators in Complex Natural Product Mixtures: A Case Study with Five Closely Related Licorice Species

Computational Tools to Expedite the Identification of Potential PXR Modulators in Complex Natural Product Mixtures: A Case Study with Five Closely Related Licorice Species

The acute toxic effect of Chinese medicine Fuzi is exacerbated in kidney yang deficiency mice due to metabolic difference

Evaluation of the Herb–Drug Interaction (HDI) Potential of Zingiber officinale and Its Major Phytoconstituents

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