Herbal Modulation of P-Glycoprotein

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.
Drug Metabolism Reviews (Impact Factor: 5.36). 03/2004; 36(1):57-104. DOI: 10.1081/DMR-120028427
Source: PubMed


P-glycoprotein (Pgp) is a 170 kDa phosphorylated glycoprotein encoded by human MDR1 gene. It is responsible for the systemic disposition of numerous structurally and pharmacologically unrelated lipophilic and amphipathic drugs, carcinogens, toxins, and other xenobiotics in many organs, such as the intestine, liver, kidney, and brain. Like cytochrome P450s (CYP3A4), Pgp is vulnerable to inhibition, activation, or induction by herbal constituents. This was demonstrated by using an ATPase assay, purified Pgp protein or intact Pgp-expressing cells, and proper probe substrates and inhibitors. Curcumin, ginsenosides, piperine, some catechins from green tea, and silymarin from milk thistle were found to be inhibitors of Pgp, while some catechins from green tea increased Pgp-mediated drug transport by heterotropic allosteric mechanism, and St. John's wort induced the intestinal expression of Pgp in vitro and in vivo. Some components (e.g., bergamottin and quercetin) from grapefruit juice were reported to modulate Pgp activity. Many of these herbal constituents, in particular flavonoids, were reported to modulate Pgp by directly interacting with the vicinal ATP-binding site, the steroid-binding site, or the substrate-binding site. Some herbal constituents (e.g., hyperforin and kava) were shown to activate pregnane X receptor, an orphan nuclear receptor acting as a key regulator of MDR1 and many other genes. The inhibition of Pgp by herbal constituents may provide a novel approach for reversing multidrug resistance in tumor cells, whereas the stimulation of Pgp expression or activity has implication for chemoprotective enhancement by herbal medicines. Certain natural flavonols (e.g., kaempferol, quercetin, and galangin) are potent stimulators of the Pgp-mediated efflux of 7,12-dimethylbenz(a)-anthracene (a carcinogen). The modulation of Pgp activity and expression by these herb constituents may result in altered absorption and bioavailability of drugs that are Pgp substrates. This is exemplified by increased oral bioavailability of phenytoin and rifampin by piperine and decreased bioavailability of indinavir, tacrolimus, cyclosporine, digoxin, and fexofenadine by coadministered St. John's wort. However, many of these drugs are also substrates of CYP3A4. Thus, the modulation of intestinal Pgp and CYP3A4 represents an important mechanism for many clinically important herb-drug interactions. Further studies are needed to explore the relative role of Pgp and CYP3A4 modulation by herbs and the mechanism for the interplay of these two important proteins in herb-drug interactions.

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    • "In the case of valerian (Table 1), preclinical data predicting drug–botanical dietaryBilberry (Vaccinium myrtillus) OATP2B1 (Mao et al., 2013Stout and Cimino, 2014) — — — Dandelion (Taraxacum spp.) CYP1A2 (Maliakal and Wanwimolruk, 2001) UDPGT (Zhou et al., 2004) — — — Dong quai (Angelica sinensis) a,b CYP1A (Lin et al., 1998); CYP3A4 (Guo et al., 2001) CYP2D6 (Tang et al., 2006); CYP3A4 (Gurley et al., 2006)— — — Evening primrose oil (Oenothera biennis) a Cis-linoleic acid: CYP1A2 (Zou et al., 2002); CYP2C9, CYP2C19, CYP2D6, CYP3A4 (Netsch et al., 2006Yuan et al., 2014); CYP2C8, CYP2C9, CYP2C19 (Whitten et al., 2006)— — — — Licorice root (Glycyrrhiza glabra, G. uralensis, and G. inflate) a CYP2A1 (Paolini et al., 1999); CYP2B6, CYP2C8, CYP2C9, CYP2C19 (Johne et al., 1999;Lefebvre et al., 2004); CYP3A4 (Johne et al., 1999;Gorski et al., 2004;Lefebvre et al., 2004); UGT1A1 (Guo et al., 2013) CYP1A2 (Kent et al., 2002); CYP2B6 (Lefebvre et al., 2004)— — — Plant sterols (e.g., sitosterol) MDR1 (Nabekura et al., 2008); MRP1 (Chow et al., 2006 "
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    ABSTRACT: The use of botanical dietary supplements has grown steadily over the last 20 years despite incomplete information regarding active constituents, mechanisms of action, efficacy, and safety. An important but under-investigated safety concern is the potential for popular botanical dietary supplements to interfere with the absorption, transport and/or metabolism of pharmaceutical agents. Clinical trials of drug-botanical interactions are the gold standard and are usually carried out only when indicated by unexpected consumer side effects or, preferably, by predictive preclinical studies. For example, Phase I clinical trials have confirmed preclinical studies and clinical case reports that St. John's wort (Hypericum perforatum) induces cytochrome P450 3A4/5. However, clinical studies of most botanicals that were predicted to interact with drugs have shown no clinically significant effects. For example, clinical trials did not substantiate preclinical predictions that milk thistle (Silybum marianum) would inhibit CYP1A2, CYP2C9, CYP2D6, CYP2E1, and/or CYP3A4. Here, we highlight discrepancies between preclinical and clinical data concerning drug-botanical interactions and critically evaluate why some preclinical models perform better than others in predicting the potential for drug-botanical interactions. Gaps in our knowledge are also highlighted for the potential of some popular botanical dietary supplements to interact with therapeutic agents with respect to absorption, transport and metabolism.
    Preview · Article · Jun 2015 · Planta Medica
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    • "In contrast to inhibitors that bind the N-terminus, novobiocin derivatives that target the C-terminal domain slow the growth of cancer cells and promote degradation of HSP90 clients without inducing the heat shock response, which is an important and somewhat unexpected distinction [80]. Other non-ATP-competitive HSP90 inhibitors are known, but most are non-selective, which limits their in vivo use; examples include epigallocatechin gallate [81] (inhibits several nonchaperone targets [82] [83] [84] [85] [86]), cisplatin [87] (damages DNA [88]), and silybin [89] (inhibits P-glycoprotein [90] and cytochrome P450 [91]). A particularly interesting class of small molecules is capable of modulating co-chaperone access to the EEVD motif in the HSP90 C-terminus. "
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    ABSTRACT: Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein folding landscape, resulting in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · May 2015 · Journal of Molecular Biology
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    • "The amount of berberine capable of crossing enterocytes seems to be reduced by about 90% by P-gp, and this suggests that either the use of a potential P-gp inhibitor21 or a chemical modification of berberine that would allow it to overcome P-gp antagonism22 might enhance its poor oral bioavailability, thus increasing its clinical effectiveness. Among the potential P-gp inhibitors, silymarin (derived from Silybum marianum), a herbal drug traditionally used as a liver protectant, could be considered a good candidate, owing to its very poor oral bioavailability and very high safety profile.23 We therefore decided to test the clinical role played by silymarin when added to berberine in the treatment of glycemic and lipid alterations in patients with T2DM. "
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    ABSTRACT: Berberine is an isoquinoline alkaloid widely used to improve the glucidic and lipidic profiles of patients with hypercholesterolemia, metabolic syndrome, and type 2 diabetes. The limitation of berberine seems to be its poor oral bioavailability, which is affected by the presence, in enterocytes, of P-glycoprotein - an active adenosine triphosphate (ATP)-consuming efflux protein that extrudes berberine into the intestinal lumen, thus limiting its absorption. According to some authors, silymarin, derived from Silybum marianum, could be considered a P-glycoprotein antagonist. The study aimed to evaluate the role played by a possible P-glycoprotein antagonist (silymarin), when added to a product containing Berberis aristata extract, in terms of benefits to patients with type 2 diabetes. The study enrolled 69 patients with type 2 diabetes in suboptimal glycemic control who were treated with diet, hypoglycemic drugs, and in cases of concomitant alterations of the lipid profile, hypolipidemic agents. The patients received an add-on therapy consisting of either a standardized extract of Berberis aristata (titrated in 85% berberine) corresponding to 1,000 mg/day of berberine, or Berberol®, a fixed combination containing the same standardized extract of Berberis aristata plus a standardized extract of Silybum marianum (titrated as >60% in silymarin), for a total intake of 1,000 mg/day of berberine and 210 mg/day of silymarin. Both treatments similarly improved fasting glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, and liver enzyme levels, whereas glycosylated hemoglobin (HbA1c) values were reduced to a greater extent by the fixed combination. The association of berberine and silymarin demonstrated to be more effective than berberine alone in reducing HbA1c, when administered at the same dose and in the form of standardized extracts in type 2 diabetic patients.
    Full-text · Article · Nov 2013 · Clinical Pharmacology: Advances and Applications
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