scholarly journals The effect of herbal materials on the p-glycoprotein activity and function

2013 ◽  
Vol 59 (4) ◽  
pp. 129-141 ◽  
Author(s):  
Anna Bogacz ◽  
Donata Deka-Pawlik ◽  
Joanna Bartkowiak-Wieczorek ◽  
Monika Karasiewicz ◽  
Radosław Kujawski ◽  
...  
Keyword(s):  
Curcuma Longa ◽  
Experimental Studies ◽  
Physiological Role ◽  
Cancer Tissue ◽  
Glycoprotein P ◽  
Synthetic Drugs ◽  
P Glycoprotein ◽  
Multidrug Resistance 1 Gene ◽  
Role Concerns ◽  
And Function

Abstract P-glycoprotein (P-gp) encoded by the MDR1 (multidrug resistance 1) gene is ATP-dependent transporting protein which is localizated in the cell membrane. P-gp is expressed mainly in organs with the secretory functions and its physiological role concerns tissue protection against xenobiotics. P-glycoprotein is involved in the permeability barriers of the blood-brain, blood-placenta directly protecting these organs. It participates in the transport of many drugs and other xenobiotics affecting their absorption, distribution, metabolism and excretion. The high P-gp activity in the cell membranes of cancer tissue is a major cause of lack of effectiveness of chemotherapy. Hence, the methods which could increase the sensibility of these pathological cells to cytostatics are still being searched. In the experimental studies it was shown that natural plant substances may have an effect on the expression level and activity of P-glycoprotein. Hypericum perforatum, Ginkgo biloba and Camellia sinensis increase P-gp activity while curcumin from Curcuma longa, piperine and silymarin inhibit this protein. Taking into account a wide substrate spectrum of P-gp, application of our knowledge on interactions of herbals and synthetic drugs should be considered in order to improve drug impact on different tissues.

scholarly journals Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 834
Author(s):  
Anima M. Schäfer ◽  
Henriette E. Meyer zu Schwabedissen ◽  
Markus Grube
Keyword(s):  
Organic Anion ◽  
Physiological Role ◽  
Point Of View ◽  
Efflux Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Current State ◽  
P Glycoprotein ◽  
The Central Nervous System ◽  
And Function ◽  
Uptake Transporters

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples.

scholarly journals Curcumin: Phytochemical Therapy in the Treatment of Hyperlipidemia

2019 ◽  
Keyword(s):  
Side Effects ◽  
Curcuma Longa ◽  
Experimental Studies ◽  
Lipid Lowering ◽  
Modern World ◽  
Therapeutic Effects ◽  
Synthetic Drugs ◽  
Wide Range

In modern world, hyperlipidemia is the most common disorder mainly caused by lifestyle habits and the major cause of cardiovascular, coronary and atherosclerotic changes. Such disorder is characterized by abnormally elevated levels of any or all lipids or lipoproteins in the blood. A wide range of drugs are available for the treatment of hyperlipidemia, class of antihyperlipidemic drugs, but such drug-therapies are carried out with presence of various side effects. In the last decades, different in vitro and in vivo research have been conducted to confirm the therapeutic effects of various phytochemical agents that overcome the side effects caused by synthetic drugs. According to Ayurvedic recommendations and experimental studies, numerous phytochemical agents have been reported to possess different antihyperlipidemic properties. One of the most studied phytochemical agent - curcumin, herbal polyphenol and active ingredient which can be extracted from the powder rhizome of the plant Curcuma longa, has been reported to possess a wide range of pharmacological properties such as antimicrobial, antioxidative, antiinflammatory and anticancer property. Recent studies also suggests curcumin as potential lipid lowering candidate in treatment of hyperlipidemia. The aim of this review is to present and discuss phytochemistry, molecular mechanism of hypolipidemic activity of curcumin, demonstrating its importance as potential therapy for the treatment of hyperlipidemia.

scholarly journals Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Hyun-Jong Cho ◽  
In-Soo Yoon
Keyword(s):  
Cytochrome P450 ◽  
Glycoprotein P ◽  
Metabolizing Enzymes ◽  
Herbal Products ◽  
P Glycoprotein ◽  
Concurrent Use ◽  
Substrate Drug ◽  
And Function

The concurrent use of drugs and herbal products is becoming increasingly prevalent over the last decade. Several herbal products have been known to modulate cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) which are recognized as representative drug metabolizing enzymes and drug transporter, respectively. Thus, a summary of knowledge on the modulation of CYP and P-gp by commonly used herbs can provide robust fundamentals for optimizing CYP and/or P-gp substrate drug-based therapy. Herein, we review ten popular medicinal and/or dietary herbs as perpetrators of CYP- and P-gp-mediated pharmacokinetic herb-drug interactions. The main focus is placed on previous works on the ability of herbal extracts and their phytochemicals to modulate the expression and function of CYP and P-gp in severalin vitroandin vivoanimal and human systems.

scholarly journals Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein

2018 ◽  
Vol 150 (3) ◽  
pp. 417-429 ◽  
Author(s):  
Estefania Barreto-Ojeda ◽  
Valentina Corradi ◽  
Ruo-Xu Gu ◽  
D. Peter Tieleman
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Experimental Studies ◽  
Lipid Binding ◽  
Coarse Grained ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Dynamics Simulations ◽  
Positively Charged ◽  
Coarse Grained Molecular Dynamics

P-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids, and lipid-like molecules. Because of its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance. Although P-gp is one of the most studied ABC transporters, the mechanism by which its substrates access the cavity remains unclear. In this study, we perform coarse-grained molecular dynamics simulations to explore possible lipid access pathways in the inward-facing conformation of P-gp embedded in bilayers of different lipid compositions. In the inward-facing orientation, only lipids from the lower leaflet access the cavity of the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid-binding sites at the portals and within the cavity, which is in good agreement with previous experimental studies. This work includes several examples of lipid pathways for phosphatidylcholine and phosphatidylethanolamine lipids that help elucidate the molecular mechanism of lipid binding in P-gp.

209. P-glycoprotein limits activation of the glucocorticoid receptor in placental BeWo cells

2005 ◽  
Vol 17 (9) ◽  
pp. 80
Author(s):  
P. J. Mark ◽  
B. J. Waddell
Keyword(s):  
Glucocorticoid Receptor ◽  
Cell Line ◽  
Pcr Analysis ◽  
Target Cells ◽  
Glycoprotein P ◽  
Bewo Cells ◽  
P Glycoprotein ◽  
Growth Inhibitory ◽  
Induced Apoptosis ◽  
And Function

Inadequate placental growth and function are key determinants of fetal growth retardation. Glucocorticoids potently inhibit fetal and placental growth via activation of the glucocorticoid receptor (GR). Placental and fetal glucocorticoid exposure is minimised by the ‘placental glucocorticoid barrier’, which consists primarily of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) converting maternal glucocorticoids to inactive metabolites. Recent studies in the rodent brain show that P-glycoprotein (P-gp) is also an important physiological regulator of glucocorticoid access to the GR in target cells. Therefore, we hypothesised that placental P-gp may serve to exclude maternal glucocorticoids from the placenta and fetus, and thereby augment the barrier. We have used the placental choriocarcinoma cell line BeWo, and MDR-BeWo, a daughter cell line virally transduced with P-gp, to assess whether P-gp regulates access of dexamethasone to the GR. Quantitative PCR analysis showed that MDR-BeWo cells express ~10-fold higher levels of P-gp mRNA than BeWo cells. Syncytialisation of BeWo and MDR-BeWo cells with 20μM forskolin also increased P-gp mRNA by ~7-fold in each cell line. The elevated P-gp expression in MDR-BeWo cells resulted in a reduced activation of the GR with 1μM dexamethasone by ~50% (P<0.001) in comparison to BeWo cells. Accordingly, dexamethasone-induced apoptosis was reduced in MDR-BeWo cells, as indicated by a lack of induction of cleaved caspase 3 protein. Additionally, the P-glycoprotein inhibitor cyclosporin A (10μM) did not increase the level of dexamethasone-induced GR activation in the low P-gp expressing BeWo cells, but potentiated GR activation by ~2-fold in the MDR-BeWo cells, to a level comparable to that in BeWo cells. These data support the hypothesis that P-glycoprotein contributes to the placental glucocorticoid barrier. Thus, 11β-HSD2 and P-glycoprotein are likely to act in unison to reduce fetal and placental exposure to maternal glucocorticoids and minimise their growth inhibitory actions.

scholarly journals Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

2019 ◽  
Vol 20 (8) ◽  
pp. 1966 ◽  
Author(s):  
Yujuan Zhang ◽  
Li Guo ◽  
Jinhu Huang ◽  
Yong Sun ◽  
Fang He ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Effect ◽  
In Vitro Models ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
And Function ◽  
Xenobiotic Receptor

Overcoming P-glycoprotein (P-gp) efflux is a strategy to improve the absorption and pharmacokinetics of its substrate drugs. Berberine inhibits P-gp and thereby increases the bioavailability of the P-gp substrate digoxin in rodents. However, the effects of berberine on P-gp in chickens are still unclear. Here, we studied the role of berberine in modulating broilers P-gp expression and function through both in situ and in vitro models. In addition, molecular docking was applied to analyze the interactions of berberine with P-gp as well as with chicken xenobiotic receptor (CXR). The results showed that the mRNA expression levels of chicken P-gp and CXR decreased in the ileum following exposure to berberine. The absorption rate constant of rhodamine 123 increased after berberine treatment, as detected using an in situ single-pass intestinal perfusion model. Efflux ratios of P-gp substrates (tilmicosin, ciprofloxacin, clindamycin, ampicillin, and enrofloxacin) decreased and the apparent permeability coefficients increased after co-incubation with berberine in MDCK-chAbcb1 cell models. Bidirectional assay results showed that berberine could be transported by chicken P-gp with a transport ratio of 4.20, and this was attenuated by verapamil (an inhibitor of P-gp), which resulted in a ratio of 1.13. Molecular docking revealed that berberine could form favorable interactions with the binding pockets of both CXR and P-gp, with docking scores of −7.8 and −9.5 kcal/mol, respectively. These results indicate that berberine is a substrate of chicken P-gp and down-regulates P-gp expression in chicken tissues, thereby increasing the absorption of P-gp substrates. Our findings suggest that berberine increases the bioavailability of other drugs and that drug-drug interactions should be considered when it is co-administered with other P-gp substrates with narrow therapeutic windows.

Shedding light on drug transport: structure and function of the P-glycoprotein multidrug transporter (ABCB1)This paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 979-992 ◽  
Author(s):  
Frances J. Sharom
Keyword(s):  
Lipid Bilayer ◽  
Drug Transport ◽  
Atp Hydrolysis ◽  
Physiological Role ◽  
Structure And Function ◽  
Drug Uptake ◽  
Spectroscopic Techniques ◽  
Binding Domains ◽  
P Glycoprotein ◽  
And Function

P-glycoprotein (Pgp; ABCB1), a member of the ATP-binding cassette (ABC) superfamily, exports structurally diverse hydrophobic compounds from the cell, driven by ATP hydrolysis. Pgp expression has been linked to the efflux of chemotherapeutic drugs in human cancers, leading to multidrug resistance (MDR). The protein also plays an important physiological role in limiting drug uptake in the gut and entry into the brain. Substrates partition into the lipid bilayer before interacting with Pgp, which has been proposed to function as a hydrophobic vacuum cleaner. Low- and medium-resolution structural models of Pgp suggest that the 2 nucleotide-binding domains are closely associated to form a nucleotide sandwich dimer. Pgp is an outwardly directed flippase for fluorescent phospholipid and glycosphingolipid derivatives, which suggests that it may also translocate drug molecules from the inner to the outer membrane leaflet. The ATPase catalytic cycle of the protein is thought to proceed via an alternating site mechanism, although the details are not understood. The lipid bilayer plays an important role in Pgp function, and may regulate both the binding and transport of drugs. This review focuses on the structure and function of Pgp, and highlights the importance of fluorescence spectroscopic techniques in exploring the molecular details of this enigmatic transporter.

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