• Title, Summary, Keyword: P-glycoprotein

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Effects of a Glycoprotein Isolated from Ulmus davidiana Nakai on Toluene-Induced Ecotoxicity and its Mechanism in Human Intestinal Epithelial Cells (소장상피세포에 있어서 느릅나무 당단백질이 톨루엔에 의해 유도된 환경독성 기작에 미치는 효과)

  • Kim, Do-Wan;Kim, Ji-Yun;Park, Moon-Ki;Lee, Sei-Jung
    • Journal of Environmental Science International
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    • v.28 no.2
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    • pp.249-257
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    • 2019
  • Ulmus davidiana Nakai (UDN) has been traditionally used as a herbal medicine to treat inflammatory diseases in Korea. In the present study, we investigated the anti-ecotoxic potential of a 116 kDa glycoprotein isolated from UDN (UDN glycoprotein) in human intestinal epithelial INT-407 cells. We demonstrated that UDN glycoprotein ($20{\mu}g/mL$) could inhibit the production of lactate dehydrogenase (LDH) induced by toluene, an ecotoxic substance. Additionally, we found that the toluene-induced intestinal cytotoxicity was mediated by the phosphorylation of p38 Mitogen-Activated Protein Kinase (MAPK) via the production of intracellular Reactive Oxygen Species (ROS). The UDN glycoprotein significantly decreased the levels of ROS production and p38 MAPK activation in toluene-stimulated INT-407 cells. Moreover, the UDN glycoprotein inhibits the phosphorylation of nuclear factor-kappa B ($NF-{\kappa}B$), which is responsible for the production of LDH, in toluene-stimulated INT-407 cells. Collectively, our data indicate that UDN glycoprotein is a natural antioxidant and a modulator of ecotoxicity signaling pathways in human intestinal epithelial cells.

Evaluating the Regulation of P-glycoprotein by Phytochemicals Using Caco-2 Cell Permeability Assay System

  • Choi, Ran Joo;Kim, Yeong Shik
    • Natural Product Sciences
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    • v.20 no.1
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    • pp.1-6
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    • 2014
  • P-glycoprotein (P-gp) is a permeability glycoprotein also known as multidrug resistance protein 1 (MDR1). P-gp is an ATP-binding cassette (ABC) transporter that pumps various types of drugs out of cells. These transporters reduce the intracellular concentrations of drugs and disturb drug absorption. The Caco-2 cell permeability assay system is an effective in vitro system that predicts the intestinal absorption of drugs and the functions of enzymes and transporters. Rhodamine-123 (R-123) and digoxin are well-known P-gp substrates that have been used to determine the function of P-gp. Efflux of P-gp substrates by P-gp has been routinely evaluated. To date, a number of herbal medicines have been tested with Caco-2 cell permeability assay system to assess bioavailability. There are growing efforts to find phytochemicals that potentially regulate P-gp function. The Caco-2 cell permeability assay system is a primary strategy to search for candidates of P-gp inhibitors. In this mini review, we have summarized the P-gp modulation by herbal extracts, decoctions or single components from natural products using Caco-2 cell permeability assays. Many natural products are known to regulate P-gp and herbal medicines could be used in combination with conventional drugs to enhance bioavailability.

in vitro Modulation of P-glycoprotein, MRP-1 and BCRP Expression by Mangiferin in Doxorubicin-Treated MCF-7 Cells

  • Louisa, Melva;Soediro, Tjahjani Mirawati;Suyatna, Frans Dhyanagiri
    • Asian Pacific Journal of Cancer Prevention
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    • v.15 no.4
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    • pp.1639-1642
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    • 2014
  • The multidrug resistance phenotype is one of the major problems in development of cancer cell resistance to chemotherapy. Some natural compounds from medicinal plants have demonstrated promising capacity in enhancing anticancer effects in drug resistant cancer cells. We aimed to investigate whether mangiferin might have an ability to re-sensitize MCF-7 breast cancer cells previously treated with short-term doxorubicin in vitro, through the modulation of efflux transporters, P-glycoprotein (P-gp), MRP1 and BCRP. We exposed MCF-7 breast cancer cells pretreated with doxorubicin for 10 days to mangiferin (10, 25 or 50 ${\mu}M$) for 96 hours. Afterwards, we evaluated influence on cell viability and level of mRNA expression of P-gp, MRP1 and BCRP. Doxorubicin given in combination with mangiferin at low concentrations (10 and 25 ${\mu}M$) failed to give significant reduction in cell viability, while at the highest concentrations, the combination significantly reduced cell viability. The mRNA expression analysis of P-gp, MRP1 and BCRP showed that mangiferin had inhibitory effects on P-gp but no effects on MRP1 and BCRP. In conclusion, we suggest that mangiferin at high concentrations can be used as chemosensitizer for doxorubicin therapy. This effect might be attributed by inhibitory effects of mangiferin on P-glycoprotein expression.

Modulation of Multidrug Resistance in Cancer by P-Glycoprotein

  • Gadhe, Changdev G.;Cho, Seung Joo
    • Journal of the Chosun Natural Science
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    • v.4 no.1
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    • pp.23-30
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    • 2011
  • Multidrug resistance (MDR) is one of the main obstacles in the chemotherapy of cancer. MDR is associated with the over expression of P-glycoprotein (P-gp), resulting in increased efflux of chemotherapy from cancer cells. Inhibiting P-gp as a method to reverse MDR in cancer patients has been studied extensively, but the results have generally been disappointing. First-generation agents were limited by unacceptable toxicity, whereas second-generation agents had better tolerability but were confounded by unpredictable pharmacokinetic interactions and interactions with other transporter proteins. Third-generation inhibitors have high potency and specificity for P-gp. Furthermore, pharmacokinetic studies to date have shown no appreciable impact on drug metabolism and no clinically significant drug interactions with common chemotherapy agents. Third-generation P-gp inhibitors have shown promise in clinical trials. The continued development of these agents may establish the true therapeutic potential of P-gp-mediated MDR reversal.

Enhancing Activity of Anticancer Drugs in Multidrug Resistant Tumors by Modulating P-Glycoprotein through Dietary Nutraceuticals

  • Khan, Muhammad;Maryam, Amara;Mehmood, Tahir;Zhang, Yaofang;Ma, Tonghui
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.16
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    • pp.6831-6839
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    • 2015
  • Multidrug resistance is a principal mechanism by which tumors become resistant to structurally and functionally unrelated anticancer drugs. Resistance to chemotherapy has been correlated with overexpression of p-glycoprotein (p-gp), a member of the ATP-binding cassette (ABC) superfamily of membrane transporters. P-gp mediates resistance to a broad-spectrum of anticancer drugs including doxorubicin, taxol, and vinca alkaloids by actively expelling the drugs from cells. Use of specific inhibitors/blocker of p-gp in combination with clinically important anticancer drugs has emerged as a new paradigm for overcoming multidrug resistance. The aim of this paper is to review p-gp regulation by dietary nutraceuticals and to correlate this dietary nutraceutical induced-modulation of p-gp with activity of anticancer drugs.

Analysis of fusogenic activity of autographa californica nuclear polyhedrosis virus (Ac NPV) gp64 envelope glycoprotein

  • Kim, Hee-Jin;Yang, Jai-Myung
    • Journal of Microbiology
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    • v.34 no.1
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    • pp.7-14
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    • 1996
  • Teh baculovirus gp64 glycoprotein is a major component of the envelope of budded virus (BV) and has been shown that it plays an essential role in the infection process, especially virus-cell membrane fusion. We have cloned Autographa californica Nuclear Polyhedrosis Virus (AcNPV) gp64 protein were examined for membrane fusion activity by using a synchtium formation assay under various conditions. The optimal conditions required for inducing membrane fusion are 1) form pH 4.0 to 4.8 2) 15 min exposure of cells to acidic pH 3) at least 1 .mu.g of gp64 cloned plasmid DNA per 3 * 10$^{6}$ cells 4) and an exposure of cells to acidic pH at 72 h post-transfection. In order to investigate the role of hydrophobicity of the gp64 glycoprotein for the membrane fusion, the two leucine residues (amino acid position at 229 and 230) within hydrophobic region I were substituted to alanine by PCR-derived site-directed mutagenisis and the membrane fusion activity of the mutant was anlaysed. The gp64 glycoprotein carrying double alamine substitution mutation showed no significant difference in fusion activity. This result suggested that minor changes in hydrophobicity at the amino acid position 229 and 230 does not affect the acid-induced membrane fusion activity of the gp64 glycoprotein.

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Evaluation on the P-Glycoprotein Inhibitory Activity of Indonesian Medicinal Plants

  • Go, Eun-Jung;Kim, Hyang-Rim;Chung, Soo-Yeon;Jeong, Yeon-Hee;Kim, Na-Hyung;Han, Ah-Reum;Seo, Eun-Kyoung;Lee, Hwa-Jeong
    • Natural Product Sciences
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    • v.10 no.2
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    • pp.85-88
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    • 2004
  • One hundred Indonesian plant extracts were screened to investigate their effects on the P-glycoprotein (P-gp) activity in human uterine sarcoma cells, MES-SA/DX5, for the first time. Among others, four samples, Alpinia galanga (BuOH ext.), Sindora sumatrana $(CHCl_3\;ext.)$, Strychnos ligustrina $(CHCl_3\;ext.)$, and Zingiber cassumunar Roxb (hexane ext.), exhibited the most potent inhibition on the P-gp activity. They increased cytotoxic activity of daunomycin up to $IC_{50}$ values of less than $1.41\;{\mu}M$, which is a value with a positive control, verapamil. Other 25 samples showed significant P-gp inhibitory activity with $IC_{50}$ values between 1.4 and $4.0\;{\mu}M$. These prospective samples will be subjected to further laboratory phytochemical investigation to find active principles.

Pharmacodynamic and pharmacokinetic interactions between herbs andwestern drugs

  • Lee, Ju-Young
    • Oriental Pharmacy and Experimental Medicine
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    • v.8 no.3
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    • pp.207-214
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    • 2008
  • In recent years, the combined use of Herbal medicines and Western drugs has been increasing. Though certain problems may occur when both types of medicines are taken together, they havenot been adequately analyzed. It was reported that anticoagulation was enhanced in addition tobleeding when patients took long-term warfarin therapy in combination with Salvia miltiorrhiza(danshen), and laxative herbs accelerate intestinal transit and interfere with the absorption. Herbal constituents, curcumin, ginsenosides, piperine, catechins and silymarin were found to beinhibitors of P-glycoprotein. St John's wort induces the intestinal expression of P-glycoprotein. Anthraquinone, quercetin and coumarins were found to be a potent inhibitor of P-450. Glycyrrhizin or liquorice extracts, Garlic and St John's wort are a potent inducer of CYP3A4. This review provides a critical overview of interactions between herbal medicines and other drugs. Hence, it is necessary to study the pharmacodynamic and pharmacokinetic interactions of many herbal medicines between western drugs.

Hypolipidemic Effects of Glycoprotein Isolated from Ficus Carica Linnoeus in Mice (무화과 당단백질의 혈중지질 저하 효과)

  • Lim, Kye-Taek;Lee, Sei-Jung;Ko, Jeong-Hyeon;Oh, Phil-Sun
    • Korean Journal of Food Science and Technology
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    • v.37 no.4
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    • pp.624-630
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    • 2005
  • Glycoprotein (60 kDa) isolated from Ficus Carica Linnoeus (FCL glycoprotein) was examined by evaluating its hypolipidemic effects on plasma cholesterol levels and hepatic detoxicant enzyme activities in ICR mice. FCL glycoprotein $(100{\mu}g/mL)$ had strong scavenging activities (38%) against lipid peroxyl radicals. When mice were treated with Triton WR-1339 (400 mg/kg), levels of total cholesterol (TC) and low-density lipoprotein (LDL)-cholesterol in plasma significantly increased by 53.9 and 47.5 mg/dL, respectively, compared to the control, whereas, when pretreated with FCL glycoprotein $(100{\mu}g/mL)$, decreased remarkably by 55.4, and 47,0 mg/dL, compared to Triton WR-1339 treatment alone. Interestingly, high-density lipoprotein (HDL)-cholesterol level did not change. Body and liver weights did not change significantly after Triton WR-1339 treatment in presence of FCL glycoprotein. FCL glycoprotein $(100{\mu}g/mL)$ stimulated activities of antioxidative detoxicant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), whereas GPx activity significantly increased compared to the control. These results suggest FCL glycoprotein has abilities to scavenge lipid peroxyl radicals, lower plasma lipid levels, and stimulate detoxicant enzyme activity in mouse liver.

P-Glycoprotein-Based Drug-Drug Interactions: Preclinical Methods and Relevance to Clinical Observations

  • Aszalos, Adorjan
    • Archives of Pharmacal Research
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    • v.27 no.2
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    • pp.127-135
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    • 2004
  • Multiple drug administration is common in elderly, HIV, and cancer patients. Such treatments may result in drug-drug interactions due to interference at the metabolic enzyme level, and due to modulation of transporter protein functions. Both kinds of interference may result in altered drug distribution and toxicity in the human body. In this review, we have dealt with drug-drug interactions related to the most studied human transporter, P-glycoprotein. This transporter is constitutively expressed in several sites in the human body. Its function can be studied in vitro with different cell lines expressing P-glycoprotein in experiments using methods and equipment such as flow cytometry, cell proliferation, cell-free ATP as activity determination and Transwell culture equipment. In vivo experiments can be carried out by mdr1a(-/-) animals and by noninvasive methods such as NMR spectrometry. Some examples are also given for determination of possible drug-drug interactions using the above-mentioned cell lines and methods. Such preclinical studies may influence decisions concerning the fate of new drug candidates and their possible dosages. Some examples of toxicities obtained in clinics and summarized in this review indicate careful consideration in cases of polypharmacy and the requirement of preclinical studies in drug development activities.