Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes

Dunkoksung, Wilasinee; Vardhanabhuti, Nontima; Siripong, Pongpun; Jianmongkol, Suree

doi:10.1124/dmd.118.085647

Cited by 9 publications

(11 citation statements)

References 52 publications

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“…Although the molecular mechanisms of HDIs are diverse, most cases of the clinically relevant HDIs are related with pharmacokinetic alterations (Qin et al, 2017;Sun et al, 2017;Dunkoksung et al, 2019;Ge, 2019), in which co-administrated herbal products alter the function or expression of drug metabolizing enzymes or transporters that are responsible for the elimination of the therapeutic agents. Unfortunately, to date, the interactions between the major constituents in Ophiopogonis Radix and drug-metabolizing enzymes in humans are rarely investigated.…”

Section: Discussionmentioning

confidence: 99%

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

Mao

Zhang

et al. 2021

Drug Metab Dispos

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Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl (MDP) moiety, is one of the major consitituents in the Chinese herb Ophiopogon japonicas. This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes, as well as to decipher the molecular mechanisms for CYP inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYPs1A, 2C8, 2C9, 2C19 and 3A in human liver microsomes (HLMs) in a reversible way, with IC 50 values varying from 1.06 μM to 3.43 μM. By contrast, MOA time-, concentrationand NADPH-dependently inhibited CYP2D6 and CYP2E1, along with K I and k inact values of 207 µM and 0.07 min -1 for CYP2D6, as well as 20.9 µM and 0.03 min -1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by GSH in a HLM incubation system, while CYPs2D6, 1A2 and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-qunione intermediate.Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYPs1A, 2C8, 2C9, 2C19 and 3A but acts as an inactivator of CYP2D6 and CYP2E1.

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Section: Discussionmentioning

confidence: 99%

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

Mao

Zhang

et al. 2021

Drug Metab Dispos

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“…It is well known that pharmacokinetic interactions are the major cause of clinically relevant HDIs [ 25 , 44 , 45 ], whereby herbal medicines modulate the pharmacokinetic behavior of co-administered Western drug(s) by regulating the expression or function of DMEs and transporters responsible for the metabolic elimination of victim Western drug(s). Because most marketed Western antiviral drugs (Table S7 , such as oseltamivir, remdesivir, and lopinavir) are predominantly metabolized by phase I DMEs, including P450s and CESs [ 27 – 29 ], this study focused on assessing potential HDIs between HEJG and antiviral Western drugs via inhibition or inactivation of phase I DMEs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb–drug interactions in antiviral therapy

et al. 2021

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Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb–drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae , as well as quercetin and kaempferol in Folium Llicis Purpureae , to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb–drug combinations for antiviral therapy in a scientific and reasonable way.

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“…2A), as previously described. 14,22,23) MCF-7/DOX cells were maintained in RPMI-1640 medium supplemented with 10% FBS, 1% penicillin/streptomycin and 1.5 µM doxorubicin at 37 °C in a humidified atmosphere of 5% CO 2 . One week before the experiments, MCF-7/DOX cells were cultured in DOX-free RPMI-1640 complete medium.…”

Section: Methodsmentioning

confidence: 99%

“…Following the treatment, the cells were harvested and total cellular protein was extracted as described previously. 14) Equal amounts of protein sample (30 µg) were separated by 10-15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and then electrophoretically transferred to a PVDF membrane. After blocking with 5% skim milk, the membranes were incubated with primary antibodies (1 : 1000) at 4 °C overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Previously, we demonstrated that rhinacanthin-C, a major naphthoquinone ester from Rhinacanthus nasutus (L.) Kurz (Acanthaceae), enhanced doxorubicin cytotoxicity in breast cancer (MCF-7) and doxorubicin-resistant MCF-7 (MCF-7/DOX) cells through direct inhibition of P-glycoprotein (P-gp) function. [14][15][16] This naphthoquinone exhibited various pharmacological activities, including anti-inflammatory, antifungal, antibacterial, antiviral and cytotoxic activities, 17,18) that contribute to the efficacy of R. nasutus in the treatment of inflammation, hepatitis, and cancer, such as cervical and liver cancers. 19) Rhinacanthin-C has been known to inhibit cell proliferation and induce apoptosis in HeLS3 and KKU-M156 cells, possibly via inhibition of the Akt/nuclear factor-kappaB (NF-κB) or ERK1/2 signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis Inducing Activity of Rhinacanthin-C in Doxorubicin-Resistant Breast Cancer MCF-7 Cells

Chaisit

Jianmongkol

2021

Biological & Pharmaceutical Bulletin

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Rhinacanthin-C is a natural bioactive naphthoquinone ester with potential chemotherapeutic value in cancer treatment. In this study, we investigated its apoptotic induction ability and the involved mechanisms through the mitogen-activated protein kinases (MAPK) and protein kinase B/glycogen synthase kinase-3β/ nuclear factor erythroid 2-related factor 2 (Akt/GSK-3β/Nrf2) signaling pathways in doxorubicin-resistant breast cancer MCF-7 (MCF-7/DOX) cells. Our 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that rhinacanthin-C (3-28 µM) significantly decreased the viability of MCF-7/DOX cells and potentiated hydrogen peroxide cytotoxicity. This naphthoquinone was able to increase intracellular reactive oxygen species (ROS), as measured by the 2′,7′-dichlorofluorescein diacetate (DCFH-DA) assay. This compound increased the number of apoptotic cells by elevating the ratio of apoptotic checkpoint proteins Bax/Bcl-2 and by decreasing the expression of poly(ADP-ribose) polymerase (PARP) protein. Furthermore, Western blotting analyses showed that treatment with rhinacanthin-C (3-28 µM) for 24 h significantly decreased the expression levels of the phosphorylated forms of MAPK proteins (i.e., extracellular signal regulated protein kinase 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38), Akt, GSK-3β and Nrf2 proteins in MCF-7/DOX cells. Inhibition of the Akt/GSK-3β/Nrf2 pathway led to a significant reduction in heme oxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide phosphate (NADP)(H): quinone oxidoreductase 1 (NQO1) proteins. These findings suggested that rhinacanthin-C was able to induce apoptosis in MCF-7/DOX cells through increased ROS production and suppression of the cell survival systems mediated by the MAPKs and Akt/GSK-3β/Nrf2 signaling pathways.

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Rhinacanthin-C Mediated Herb-Drug Interactions with Drug Transporters and Phase I Drug-Metabolizing Enzymes

Cited by 9 publications

References 52 publications

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

Reversible and Irreversible Inhibition of Cytochrome P450 Enzymes by Methylophiopogonanone A

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb–drug interactions in antiviral therapy

Apoptosis Inducing Activity of Rhinacanthin-C in Doxorubicin-Resistant Breast Cancer MCF-7 Cells

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