Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84)

Haslam, Iain S.; Jones, Karen L.; Coleman, Tanya; Simmons, Nicholas L.

doi:10.1016/j.bcp.2008.07.020

Cited by 62 publications

(45 citation statements)

References 59 publications

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“…The permeability/efflux ratios of digoxin with Pgp in several cell lines ranged between 4 and 35 [21,24,102,103]. This contrasts with the permeability/efflux ratios for Pgp at low verapamil concentrations, which were generally lower and ranged from ∼1 to 6 [21,23,24]. These results suggest that the coupling between ATP hydrolysis and transport for drugs may be ligand dependent.…”

Section: Discussionmentioning

confidence: 74%

“…Therefore, Pgp will be in an intermediate conformation in our model. The permeability/efflux ratios of digoxin with Pgp in several cell lines ranged between 4 and 35 [21,24,102,103]. This contrasts with the permeability/efflux ratios for Pgp at low verapamil concentrations, which were generally lower and ranged from ∼1 to 6 [21,23,24].…”

Section: Discussionmentioning

confidence: 77%

“…From results of in vitro studies, the drug is known to activate Pgp-coupled ATP-hydrolysis [20]. This drug manifests a spectrum of characteristics, ranging from being a good substrate to a non-substrate for the transporter, which depends on the cell type being evaluated in in vitro cell studies [21][22][23][24][25][26] or host tissue type in in vivo studies [27][28][29]. Although the actual molecular details of these interactions are currently unknown, the drug has been shown to inhibit the ATPase activity of a second drug by competitive, non-competitive and allosteric mechanisms in an in vitro study [30].…”

Section: Introductionmentioning

confidence: 99%

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Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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SynopsisDrug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

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Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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“…And HIEC may have a number of different applications (36). For example, they can be used to evaluate the effects of growth or maturation factors on the expression of membrane receptors and antigens, enzymatic activities, transport and secretory functions (37), to study drug metabolism, and to investigate carcinogenic factors and agonists (38). Furthermore, they contribute to growth and functional alterations of the colonic epithelium in intestinal cancers, IBD and other diseases and to the understanding of the mechanisms of interactions of intestinal pathogens with the mucosal surface (39) and the intracellular signaling transduction (40).…”

Section: Discussionmentioning

confidence: 99%

Culture of human intestinal epithelial cell using the dissociating enzyme thermolysin and endothelin-3

Liu

Zhang

Zhou

et al. 2010

Braz J Med Biol Res

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Epithelium, a highly dynamic system, plays a key role in the homeostasis of the intestine. However, thus far a human intestinal epithelial cell line has not been established in many countries. Fetal tissue was selected to generate viable cell cultures for its sterile condition, effective generation, and differentiated character. The purpose of the present study was to culture human intestinal epithelial cells by a relatively simple method. Thermolysin was added to improve the yield of epithelial cells, while endothelin-3 was added to stimulate their growth. By adding endothelin-3, the achievement ratio (viable cell cultures/total cultures) was enhanced to 60% of a total of 10 cultures (initiated from 8 distinct fetal small intestines), allowing the generation of viable epithelial cell cultures. Western blot, real-time PCR and immunofluorescent staining showed that cytokeratins 8, 18 and mouse intestinal mucosa-1/39 had high expression levels in human intestinal epithelial cells. Differentiated markers such as sucrase-isomaltase, aminopeptidase N and dipeptidylpeptidase IV also showed high expression levels in human intestinal epithelial cells. Differentiated human intestinal epithelial cells, with the expression of surface markers (cytokeratins 8, 18 and mouse intestinal mucosa-1/39) and secretion of cytokines (sucrase-isomaltase, aminopeptidase N and dipeptidylpeptidase IV), may be cultured by the thermolysin and endothelin-3 method and maintained for at least 20 passages. This is relatively simple, requiring no sophisticated techniques or instruments, and may have a number of varied applications.

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“…P-gp plays an important role in regulating absorption, distribution, and elimination of drugs. P-gp has been found to mediate the energy dependent efflux of xenobiotics in epithelial tissues of the human body including the intestinal mucosa, liver, testicular membrane, and kidney proximal tubules, as well as blood-tissue-barriers such as the brain and placenta (Cigana et al 2007;Haslam et al 2008). P-gp, therefore, could decrease intestinal absorption, increase biliary excretion or renal tubular secretion, and impair drug distribution to the brain for several drugs (DeGorter et al 2012 for review).…”

Section: Introductionmentioning

confidence: 99%

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

et al. 2014

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The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications including the lipid lowering drug, atorvastatin. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the lipid lowering effect of atorvastatin among Jordanians. Lipid and lipoproteins were measured in blood samples collected from patients (n = 201) at baseline and during atorvastatin treatment. MDR1 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Both the TT genotype of G2677T and the TT genotype of the C3435T polymorphisms were associated with lower levels of low-density lipoproteins after atorvastatin treatment. However, the effects of atorvastatin on the levels of total cholesterol, triglycerides, and high-density lipoprotein, were not correlated with any of the genotypes in both polymorphisms. Finally, the C1236T polymorphism was not associated with the lipid lowering effect of atorvastatin. In conclusion, the MDR1 gene polymorphisms G2677T, and C3435T, but not C1236T were associated with the lipid lowering effect of atorvastatin among Jordanians.

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Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84)

Cited by 62 publications

References 59 publications

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Culture of human intestinal epithelial cell using the dissociating enzyme thermolysin and endothelin-3

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

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