Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

P-glykoprotein has been proposed to function as a membrane transport protein for a large variety of substrates, ranging from small lipophilic molecules, steroid hormones, lipophilic peptides, some drugs, biologically important molecules and xenobiotics. There is little doubt that P-glycoprotein transports a wide range of substrates out of cells, nevertheless it is difficult to explain its wide substrate specificity and mechanism of the transport. P-glycoprotein has been found to be a major cause of acquired multidrug resistance (MDR) of cancer cells to chemotherapeutic drugs. The identification and localization of P-glycoprotein expression in a variety of normal human tissues raised the question of the physiological functions of P-glykoprotein. Currently, there is considerable evidence that P-glycoprotein can protect the body and sensitive tissues against a range of different xenobiotics. In addition, P-glycoprotein might play a role in regulation of cell differentiation, proliferation, immune response and programmed cell death.
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PMID:[Physiologic function of P-glycoprotein]. 1240 86

Anthelmintic resistance in parasitic nematodes of livestock is a chronic problem in many parts of the world. Benzimidazoles are effective, broad-spectrum anthelmintics that bind to and selectively depolymerise microtubules. Resistance to the benzimidazoles, however, developed quickly and is caused by genetic changes in genes encoding beta-tubulins, subunits of microtubules. In Haemonchus contortus, resistance to avermectins has been correlated with genetic changes at a gene encoding a P-glycoprotein, a cell membrane transport protein that has a very high affinity for ivermectin. The substrate specificity of P-glycoprotein is very broad, and resistance to benzimidazoles can be modulated by lectins specific for P-glycoprotein. We investigated the possibility that genetic changes in P-glycoprotein might be correlated with benzimidazole resistance in nematodes. An analysis of restriction fragment length polymorphisms of a P-glycoprotein gene from a sensitive and a cambendazole-selected strain of H. contortus, derived from the sensitive strain, showed a significant difference in allele frequencies between strains. The frequency of one allele in particular increased substantially. The same allele was also found at a high frequency in an independently derived thiabendazole-selected field isolate. We present genetic evidence of selection at a P-glycoprotein locus during selection for benzimidzole resistance in H. contortus.
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PMID:P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles. 1824 94

The antidepressant activity of citalopram (R,S-CIT) is mainly due to its (S)-enantiomer (S-CIT). P-glycoprotein (P-gp), encoded by the ABCB1 gene, is a membrane transport protein which regulates the efflux of many drugs. Polymorphisms in the ABCB1 gene may have an impact on the expression and function of P-gp, thereby influencing the response to treatment with antidepressants, which are substrates of this protein. The influence of ABCB1 polymorphism on the disposition of R,S-CIT in plasma and cerebrospinal fluid (CSF) was examined under steady-state conditions in 15 patients with major depression treated with 40 mg/d R,S-CIT for 4 weeks. In contrast to the ABCB1 C3435T polymorphism, only the ABCB1 G2677T polymorphism significantly influences R,S-CIT plasma and CSF concentrations (46+/-11 ng/ml versus 69+/-20 ng/ml for TT versus GT/GG in plasma, p=0.027; 24+/-5 ng/ml versus 32+/-9 ng/ml for TT versus GT/GG in CSF, p=0.05). On the other hand, no significant influence of G2677T polymorphism was found on the plasma and CSF (S)/(R) ratio, suggesting a lack of stereoselectivity in the activity of this transporter. The 2677 GG/GT genotype was associated with a better treatment response (p=0.001) compared with 2677TT genotype. Furthermore, higher R,S-CIT plasma and CSF concentrations were observed in treatment responders. This study is the first to demonstrate that a P-gp polymorphism significantly influences plasma and CSF concentrations of R,S-CIT in depressive patients, therefore possibly influencing the activity of this antidepressant. These findings should be replicated in future studies with larger groups of patients. Because of the small number of subjects in the present study, future studies with larger groups of patients, also with different ethnicities.
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PMID:Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. 1894 Feb 59

The membrane transport protein P-glycoprotein (P-gp) is an interesting candidate for individual differences in response to antipsychotics. To present an overview of the current knowledge of P-gp and its interaction with second-generation antipsychotics (SGAs), an internet search for all relevant English original research articles concerning P-gp and SGAs was conducted. Several SGAs are substrates for P-gp in therapeutic concentrations. These include amisulpride, aripiprazole, olanzapine, perospirone, risperidone and paliperidone. Clozapine and quetiapine are not likely to be substrates of P-gp. However, most antipsychotics act as inhibitors of P-gp, and can therefore influence plasma and brain concentrations of other substrates. No information was available for sertindole, ziprasidone or zotepine. Research in animal models demonstrated significant differences in antipsychotic brain concentration and behavior owing to both P-gp knockout and inhibition. Results in patients are less clear, as several external factors have to be accounted for. Patients with polymorphisms which decrease P-gp functionality tend to perform better in clinical settings. There is some variability in the findings concerning adverse effects, and no definitive conclusions can be drawn at this point.
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PMID:Relationship between P-glycoprotein and second-generation antipsychotics. 2184 66

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for numerous chemotherapeutic agents. Multiple key regulators are alleged to be responsible for MDR and making the treatment regimens ineffective. In this review, we discuss MDR in relation to P-glycoprotein (P-gp) and its down-regulation by natural bioactive molecules. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its diverse tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus assisting in the development of MDR. Eventually, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. However, the use of synthetic inhibitors is known to cause serious toxicities. For this reason, the search for more potent and less toxic P-gp inhibitors of natural origin is underway. The present review aims to recapitulate the research findings on bioactive constituents of natural origin with P-gp inhibition characteristics. Natural bioactive constituents with P-gp modulating effects offer great potential for semi-synthetic modification to produce new scaffolds which could serve as valuable investigative tools to recognize the function of complex ABC transporters apart from evading the systemic toxicities shown by synthetic counterparts. Despite the many published scientific findings encompassing P-gp inhibitors, however, this article stand alones because it provides a vivid picture to the readers pertaining to Pgp inhibitors obtained from natural sources coupled with their mode of action and structures. It provides first-hand information to the scientists working in the field of drug discovery to further synthesise and discover new P-gp inhibitors with less toxicity and more efficacies.
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PMID:Natural Products as Alternative Choices for P-Glycoprotein (P-gp) Inhibition. 2858 82

P-glycoprotein (encoded by MDR1) is a membrane transport protein expressed in the intestine, liver, kidney, placenta, and blood-brain barrier. It excludes various clinically important drugs from cells, such as verapamil, digoxin, tacrolimus, and vinblastine. Therefore, human P-glycoprotein plays important roles in drug absorption, distribution, and excretion. We reported previously that auraptene, a natural compound occurring widely in citrus fruit (e.g., grapefruit), inhibited P-glycoprotein-mediated drug transport. In this study, we investigated the effects of auraptene and other phenylpropanoids on P-glycoprotein expression using human intestinal epithelial LS174T cells and a reporter plasmid expressing 10.2 kbp of the upstream regulatory region of MDR1. Auraptene (7-geranyloxycoumarin), a prenylated coumarin, and several phenylpropanoids, such as 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans propenoic acid, derricidin [2'-hydroxy-4'-(prenyloxy)chalcone], and 3-(4'-geranyloxyphenyl)-propanoic acid, induced MDR1 promoter activity in LS174T cells. Overexpression of the nuclear receptor human pregnane X receptor gene (NR1I2) enhanced auraptene-induced MDR1 activation. Nuclear factor-kappaB inhibitors, Bay11-7082 and JSH-23, repressed MDR1 activation by auraptene. Western blot analyses showed the induction of P-glycoprotein expression in the auraptene-treated LS174T cells. The citrus phytochemical auraptene can induce the drug efflux transporter P-glycoprotein in human intestinal cells, and thus has the potential to cause food-drug interactions.
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PMID:Citrus auraptene induces drug efflux transporter P-glycoprotein expression in human intestinal cells. 3253 Apr 47


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