Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal productsThis article is one of a selection of papers published in this special issue (part 1 of 2) on the Safety and Efficacy of Natural Health Products.

Budzinski, J.W.; Trudeau, Vance L.; Drouin, Cathy E; Panahi, Mitra; Arnason, John T.; Foster, Brian

doi:10.1139/y07-091

Cited by 35 publications

(3 citation statements)

References 29 publications

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“…Pellucidin A from P. pellucida was reported to have antimutagenic and antifungal effects against Trichophyton mentagrophytes [34]. Dillapiole has numerous reported effects; it has been found to act as a cytochrome P450 3A4 inhibitor, antibacterial agent, insecticide, antifungal agent, and anti-inflammatory agent in addition to DNA adduction activity [51][52][53][54][55][56][57]. Dillapiole that was isolated from P. pellucida was reported to have a gastroprotective effect [58].…”

Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of Phenylpropanoid and Lignan Compounds from Peperomia pellucida [L.] Kunth with Estrogenic Activities

et al. 2020

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Extracts of Peperomia pellucida [L.] Kunth have previously been demonstrated to have in vivo estrogenic-like effects, thereby functioning as an anti-osteoporotic agent. However, the compounds responsible for these effects have not yet been determined. Therefore, the aim of this study is to isolate and elucidate potential compounds with estrogenic activity. The structures of the isolated compounds were identified using 1D 1H and 13C-NMR and confirmed by 2D FT-NMR. The estrogenic activity was evaluated using the E-SCREEN assay, and a molecular docking study was performed to predict the binding affinity of the isolated compounds to estrogen receptors. In this experiment, we successfully isolated three phenylpropanoids and two lignan derivatives, namely, 6-allyl-5-methoxy-1,3-benzodioxol-4-ol (1), pachypostaudin B (2), pellucidin A (3), dillapiole (4), and apiol (5). Among these compounds, the isolation of 1 and 2 from P. pellucida is reported for the first time in this study. Activity assays clearly showed that the ethyl acetate extract and its fractions, subfractions, and isolated compounds exerted estrogenic activity. Methanol fraction of the ethyl acetate extract produced the highest estrogenic activity, while 1 and 2 had partial agonist activity. Some compounds (derivates of dillapiole and pellucidin A) also had, in addition, anti-estrogenic activity. In the docking study, the estrogenic activities of 1–5 appeared to be mediated by a classical ligand-dependent mechanism as suggested by the binding interaction between the compounds and estrogen receptors; binding occurred on Arg 394 and His 524 of the alpha receptor and Arg 346 and His 475 of the beta receptor. In summary, we reveal that P. pellucida is a promising anti-osteoporotic agent due to its estrogenic activity, and the compounds responsible for this activity were found to be lignan and phenylpropanoid derivatives. The presence of other compounds in either the extract or fraction may contribute to a synergistic effect, as suggested by the higher estrogenic activity of the methanol fraction. Hence, we suggest further research on the osteoporotic activity and safety of the identified compounds, especially regarding their effects on estrogen-responsive organs.

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Section: Discussionmentioning

confidence: 99%

Isolation and Characterization of Phenylpropanoid and Lignan Compounds from Peperomia pellucida [L.] Kunth with Estrogenic Activities

et al. 2020

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“…As for moderation of CYPs on a transcriptional level, downregulation of CYP 3A4 was only reported in Caco-2 monolayer [47], but not in primary human hepatocytes [48].…”

Section: Silybin As a Perpetrator Of Ddimentioning

confidence: 99%

Metabolism, Transport and Drug–Drug Interactions of Silymarin

Xie

Zhang

et al. 2019

Molecules

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Silymarin, the extract of milk thistle, and its major active flavonolignan silybin, are common products widely used in the phytotherapy of liver diseases. They also have promising effects in protecting the pancreas, kidney, myocardium, and the central nervous system. However, inconsistent results are noted in the different clinical studies due to the low bioavailability of silymarin. Extensive studies were conducted to explore the metabolism and transport of silymarin/silybin as well as the impact of its consumption on the pharmacokinetics of other clinical drugs. Here, we aimed to summarize and highlight the current knowledge of the metabolism and transport of silymarin. It was concluded that the major efflux transporters of silybin are multidrug resistance-associated protein (MRP2) and breast cancer resistance protein (BCRP) based on results from the transporter-overexpressing cell lines and MRP2-deficient (TR−) rats. Nevertheless, compounds that inhibit the efflux transporters MRP2 and BCRP can enhance the absorption and activity of silybin. Although silymarin does inhibit certain drug-metabolizing enzymes and drug transporters, such effects are unlikely to manifest in clinical settings. Overall, silymarin is a safe and well-tolerated phytomedicine.

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“…Herbal interactions involving the CYP3A4 enzyme and P-gp may be responsible for many cases of therapeutic failures or adverse effects already reported, especially in patients under treatment with narrow therapeutic index drugs 11 , 18 , 19 . The impact of V. officinalis and P. methysticum on the activities of CYP3A4 and P-gp is a topic of debate among different authors, with some demonstrating inhibition 20 , 21 and others no effect 22 , 23 , 24 .…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Effects of Extracts Containing Valeriana officinalis and Piper methysticum on the Activities of Cytochrome P450 3A and P-Glycoprotein

Nascimento,

do Nascimento,

Lima

et al. 2024

Planta Med

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This work investigated interactions ascribed to the administration of phytomedicines containing Valeriana officinalis and Piper methysticum with conventional drugs. The phytomedicines were characterized by HPLC and administered per os to male Wistar rats, either concomitantly or not with the CYP3A substrate midazolam. To distinguish between the presystemic or systemic effect, midazolam was given orally and intravenously. The effects on the P-gp substrate fexofenadine uptake by Caco-2 cells were examined. The valerenic acid content was 1.6 ± 0.1 mg per tablet, whereas kavain was 13.7 ± 0.3 mg/capsule. Valerian and kava-kava extracts increased the maximum plasma concentration (Cmax) of midazolam 2- and 4-fold compared to the control, respectively. The area under the plasma concentrations versus time curve (AUC(0-∞)) was enhanced from 994.3 ± 152.3 ng.h/mL (control) to 3041 ± 398 ng.h/mL (valerian) and 4139 ± 373 ng.h/mL (kava-kava). The half-life of midazolam was not affected. These changes were attributed to the inhibition of midazolam metabolism by the enteric CYP3A since the i. v. pharmacokinetic of midazolam remained unchanged. The kava-kava extract augmented the uptake of fexofenadine by 3.5-fold compared to the control. Although Valeriana increased the uptake of fexofenadine, it was not statistically significant to that of the control (12.5 ± 3.7 ng/mg protein vs. 5.4 ± 0.3 ng/mg protein, respectively). Therefore, phytomedicines containing V. officinalis or P. methysticum inhibited the intestinal metabolism of midazolam in rats. Conversely, the P-gp-mediated transport of fexofenadine was preferably affected by kava-kava.

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Cited by 35 publications

References 29 publications

Isolation and Characterization of Phenylpropanoid and Lignan Compounds from Peperomia pellucida [L.] Kunth with Estrogenic Activities

Isolation and Characterization of Phenylpropanoid and Lignan Compounds from Peperomia pellucida [L.] Kunth with Estrogenic Activities

Metabolism, Transport and Drug–Drug Interactions of Silymarin

Evaluation of the Effects of Extracts Containing Valeriana officinalis and Piper methysticum on the Activities of Cytochrome P450 3A and P-Glycoprotein

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