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Anticancer Research 2008P-glycoprotein (Pgp), encoded by the ATP-binding cassette B1 (ABCB1) gene, is an efflux transporter located on the luminal side of intestinal epithelial cells, which...
BACKGROUND
P-glycoprotein (Pgp), encoded by the ATP-binding cassette B1 (ABCB1) gene, is an efflux transporter located on the luminal side of intestinal epithelial cells, which protects the gut from endogenous and exogenous toxins. The association of two ABCB1 polymorphisms with the occurrence of colon cancer and long-term prognosis was evaluated in a selected patient population. The expression of Pgp in neoplastic and normal intestinal mucosa was also studied.
PATIENTS AND METHODS
Archival material from 51 patients, in Dukes stage B2 or C, treated for 6 months with 5-fluorouracil plus leucovorin was retrieved. The G2677T and C3435T polymorphisms were studied and immunohistochemical analysis of the tumor and adjacent normal tissue was performed.
RESULTS
The distribution of wild-type and polymorphic genotypes was similar in the patients and controls and in the patients who relapsed and those who remained event-free for 5 years. Cox proportional hazard model indicated an increased probability of relapse for older patients (p = 0.042) and C stage tumors (p = 0.030). Pgp expression was significantly lower in cancer tissue compared to normal mucosa (p < 0.001) and was related to grading, being lower in poorly-differentiated tumors (p < 0.05); however, no relationship was seen between Pgp expression, genotype and long-term prognosis.
CONCLUSION
G2677T and C3435T polymorphisms are not associated with colon cancer risk and prognosis in a selected patient population.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Aged; Biomarkers, Tumor; Colorectal Neoplasms; Female; Humans; Male; Middle Aged; Polymorphism, Genetic; Prognosis
PubMed: 19192650
DOI: No ID Found -
FEBS Letters Sep 2004P-glycoprotein is an efflux pump for a broad spectrum of hydrophobic agents. We found that bioactive peptides including somatostatin and substance P inhibit...
P-glycoprotein is an efflux pump for a broad spectrum of hydrophobic agents. We found that bioactive peptides including somatostatin and substance P inhibit ATP-dependent vincristine binding to P-glycoprotein-overexpressing K562/ADM membrane vesicles. Some of these bioactive peptides including somatostatin stimulate basal ATPase activity of P-glycoprotein; in contrast, other peptides including substance P inhibit it. The K562/ADM membrane vesicles showed an ATP-dependent, osmotically sensitive uptake of somatostatin and substance P, which was inhibited by valspodar, an inhibitor of P-glycoprotein. These findings suggested that certain bioactive peptides such as somatostatin and substance P directly interact with human P-glycoprotein as endogenous substrates for P-glycoprotein-mediated transport.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Amino Acid Sequence; Humans; Protein Transport; Somatostatin; Substance P
PubMed: 15358539
DOI: 10.1016/j.febslet.2004.07.084 -
PloS One 2013Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp) expression. Confirmation of P-gp expression...
Bioavailability is the most important factor for the efficacy of any drug and it is determined by P- glycoprotein (P-gp) expression. Confirmation of P-gp expression during ontogeny is needed for understanding the differences in therapeutic efficacy of any drug in juvenile and adult animals. In this study, Abcb1 mRNA levels in the liver and intestine of broilers during ontogeny were analysed by RT qPCR. Cellular distribution of P-gp was detected by immunohistochemstry. Age-related differences of enrofloxacin pharmacokinetics were also studied. It was found that broilers aged 4 week-old expressed significantly (P<0.01) higher levels of P-gp mRNA in the liver, jejunum and ileum, than at other ages. However, there was no significant (P>0.05) age-related difference in the duodenum. Furthermore, the highest and lowest levels of Abcb1 mRNA expression were observed in the jejunum, and duodenum, respectively. P-gp immunoreactivity was detected on the apical surface of the enterocytes and in the bile canalicular membranes of the hepatocytes. Pharmacokinetic analysis revealed that the 8 week-old broilers, when orally administrated enrofloxacin, exhibited significantly higher Cmax (1.97 vs. 0.98 μg • ml(-1), P=0.009), AUC(14.54 vs. 9.35 μg • ml(-1) • h, P=0.005) and Ka (1.38 vs. 0.43 h(-1), P=0.032), as well as lower Tpeak (1.78 vs. 3.28 h, P=0.048) and T1/2 ka (0.6 vs. 1.64 h, P=0.012) than the 4 week-old broilers. The bioavailability of enrofloxacin in 8 week-old broilers was increased by 15.9%, compared with that in 4 week-old birds. Interestingly, combining verapamil, a P-gp modulator, significantly improved pharmacokinetic behaviour of enrofloxacin in all birds. The results indicate juvenile broilers had a higher expression of P-gp in the intestine, affecting the pharmacokinetics and reducing the bioavailability of oral enrofloxacin in broilers. On the basis of our results, it is recommended that alternative dose regimes are necessary for different ages of broilers for effective therapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Aging; Animals; Chickens; Enrofloxacin; Fluoroquinolones; Intestinal Mucosa
PubMed: 24066110
DOI: 10.1371/journal.pone.0074150 -
Bioorganic & Medicinal Chemistry Sep 2012P-Glycoprotein (P-gp, ABCB1) plays a significant role in determining the ADMET properties of drugs and drug candidates. Substrates of P-gp are not only subject to...
P-Glycoprotein (P-gp, ABCB1) plays a significant role in determining the ADMET properties of drugs and drug candidates. Substrates of P-gp are not only subject to multidrug resistance (MDR) in tumor therapy, they are also associated with poor pharmacokinetic profiles. In contrast, inhibitors of P-gp have been advocated as modulators of MDR. However, due to the polyspecificity of P-gp, knowledge on the molecular basis of ligand-transporter interaction is still poor, which renders the prediction of whether a compound is a P-gp substrate/non-substrate or an inhibitor/non-inhibitor quite challenging. In the present investigation, we used a set of fingerprints representing the presence/absence of various functional groups for machine learning based classification of a set of 484 substrates/non-substrates and a set of 1935 inhibitors/non-inhibitors. Best models were obtained using a combination of a wrapper subset evaluator (WSE) with random forest (RF), kappa nearest neighbor (kNN) and support vector machine (SVM), showing accuracies >70%. Best P-gp substrate models were further validated with three sets of external P-gp substrate sources, which include Drug Bank (n = 134), TP Search (n = 90) and a set compiled from literature (n = 76). Association rule analysis explores the various structural feature requirements for P-gp substrates and inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Algorithms; Computational Biology; Databases, Pharmaceutical; Drug Substitution; Models, Molecular; Molecular Structure
PubMed: 22595422
DOI: 10.1016/j.bmc.2012.03.045 -
FEBS Letters Feb 2022A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V O ]...
A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V O ] (V ), [H V O (PO )] (V ), [V O Cl] (V ) and [V O I] (V ) as inhibitors of three major multidrug resistance-linked ABC transporters: P-glycoprotein (P-gp), ABCG2 and MRP1. All of the POVs selectively inhibited P-gp. V and V were the two most promising compounds, with IC values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC value of 1.26 µm. V and V triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V with rhodamine B, RhoB-V . The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand-binding site, opening new possibilities in the development of potent modulators of ABC transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1
PubMed: 34939198
DOI: 10.1002/1873-3468.14265 -
Drug Metabolism and Pharmacokinetics 2012Recent pharmacogenomic/pharmacogenetic (PGx) studies have disclosed important roles for drug transporters in the human body. Changes in the functions of drug... (Review)
Review
Recent pharmacogenomic/pharmacogenetic (PGx) studies have disclosed important roles for drug transporters in the human body. Changes in the functions of drug transporters due to drug/food interactions or genetic polymorphisms, for example, are associated with large changes in pharmacokinetic (PK) profiles of substrate drugs, leading to changes in drug response and side effects. This information is extremely useful not only for drug development but also for individualized treatment. Among drug transporters, the ATP-binding cassette (ABC) transporters are expressed in most tissues in humans, and play protective roles; reducing drug absorption from the gastrointestinal tract, enhancing drug elimination into bile and urine, and impeding the entry of drugs into the central nervous system and placenta. In addition to PK/pharmacodynamic (PD) issues, ABC transporters are reported as etiologic and prognostic factors (or biomarkers) for genetic disorders. Although a consensus has not yet been reached, clinical studies have demonstrated that the PGx of ABC transporters influences the overall outcome of pharmacotherapy and contributes to the pathogenesis and progression of certain disorders. This review explains the impact of PGx in ABC transporters in terms of PK/PD, focusing on P-glycoprotein and breast cancer resistance protein (BCRP).
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Biotransformation; Humans; Intestinal Absorption; Neoplasm Proteins; Pharmacokinetics; Polymorphism, Genetic; Protein Conformation; Tissue Distribution
PubMed: 22123128
DOI: 10.2133/dmpk.dmpk-11-rv-098 -
PloS One 2013Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and...
Methadone is a widely used substitution therapy for opioid addiction. Large inter-individual variability has been observed in methadone maintenance dosages and P-glycoprotein (P-gp) was considered to be one of the major contributors. To investigate the mechanism of P-gp's interaction with methadone, as well as the effect of genetic variants on the interaction, Flp-In™-293 cells stably transfected with various genotypes of human P-gp were established in the present study. The RNA and protein expression levels of human P-gp were confirmed by real-time quantitative RT-PCR and western blot, respectively. Utilizing rhodamine 123 efflux assay and calcein-AM uptake study, methadone was demonstrated to be an inhibitor of wild-type human P-gp via non-competitive kinetic (IC50 = 2.17±0.10 µM), while the variant-type human P-gp, P-gp with 1236T-2677T-3435T genotype and P-gp with 1236T-2677A-3435T genotype, showed less inhibition potency (IC50 = 2.97±0.09 µM and 4.43±1.10 µM, respectively) via uncompetitive kinetics. Methadone also stimulated P-gp ATPase and inhibited verapamil-stimulated P-gp ATPase activity under therapeutic concentrations. These results may provide a possible explanation for higher methadone dosage requirements in patients carrying variant-type of P-gp and revealed the possible drug-drug interactions in patients who receive concomitant drugs which are also P-gp substrates.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Analysis of Variance; Blotting, Western; Fluoresceins; Genetic Variation; HEK293 Cells; Humans; Immunoblotting; Inhibitory Concentration 50; Kinetics; Methadone; Mutagenesis, Site-Directed; Real-Time Polymerase Chain Reaction; Rhodamine 123; Verapamil
PubMed: 23527191
DOI: 10.1371/journal.pone.0059419 -
Journal of Lipid Research Oct 2004P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a... (Comparative Study)
Comparative Study
P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a functional association in raft microdomains will require that P-gp retains activity in the microenvironment. Purified hamster P-gp was reconstituted in liposomes comprising sphingomyelin and cholesterol, both highly enriched in membrane microdomains and known to impart a liquid-ordered phase to bilayers. The activity of P-gp was compared with that of proteoliposomes composed of crude egg phosphatidylcholine (unsaturated) or dipalmitoyl phosphatidylcholine (saturated) in the presence or absence of cholesterol. The maximal rate of ATP hydrolysis was not significantly altered by the nature of the lipid species. However, the potencies of nicardipine and XR9576 to modulate the ATPase activity of P-gp were increased in the sphingolipid-based proteoliposomes. The drug-P-gp interaction was investigated by measurement of the rates of [(3)H]XR9576 association and dissociation from the transporter. The lipid environment of P-gp did not affect these kinetic parameters of drug binding. In summary, P-gp retains function in liquid-ordered cholesterol and sphingolipid model membranes in which the communication between the transmembrane and the nucleotide binding domains after drug binding to the protein is more efficient.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Animals; CHO Cells; Cholesterol; Cricetinae; Kinetics; Liposomes; Membrane Microdomains; Models, Biological; Nicardipine; Phosphatidylcholines; Quinolines; Sphingolipids; Vanadates
PubMed: 15258203
DOI: 10.1194/jlr.M400220-JLR200 -
The Oncologist Aug 2007The importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous... (Review)
Review
The importance of P-glycoprotein (P-gp) in drug-drug interactions is increasingly being identified. P-gp has been reported to affect the pharmacokinetics of numerous structurally and pharmacologically diverse substrate drugs. Furthermore, genetic variability in the multidrug resistance 1 gene influences absorption and tissue distribution of drugs transported. Inhibition or induction of P-gp by coadministered drugs or food as well as herbal constituents may result in pharmacokinetic interactions leading to unexpected toxicities or undertreatment. On the other hand, modulation of P-gp expression and/or activity may be a useful strategy to improve the pharmacological profile of anticancer P-gp substrate drugs. In recent years, the use of complementary and alternative medicine (CAM), like herbs, food, and vitamins, by cancer patients has increased significantly. CAM use substantially increases the risk for interactions with anticancer drugs, especially because of the narrow therapeutic window of these compounds. However, for most CAMs, it is unknown whether they affect metabolizing enzymes and/or drug transporter activity. Clinically relevant interactions are reported between St John's wort or grapefruit juice and anticancer as well as nonanticancer drugs. CAM-drug interactions could explain, at least in part, the large interindividual variation in efficacy and toxicity associated with drug therapy in both cancer and noncancer patients. The study of drug-drug, food-drug, and herb-drug interactions and of genetic factors affecting pharmacokinetics and pharmacodynamics is expected to improve drug safety and will enable individualized drug therapy. Disclosure of potential conflicts of interest is found at the end of this article.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Interactions; Herb-Drug Interactions; Humans
PubMed: 17766652
DOI: 10.1634/theoncologist.12-8-927 -
Biochimica Et Biophysica Acta Oct 1996Since pesticides have been shown to interact with P-glycoprotein (P-gp), the purpose of this study was to examine the possible role of P-gp in pesticide resistance in...
Since pesticides have been shown to interact with P-glycoprotein (P-gp), the purpose of this study was to examine the possible role of P-gp in pesticide resistance in the tobacco budworm (Heliothis virescens). Using three P-gp antibodies, P-gp expression in various resistant populations of tobacco budworms was found to be 2-6-times that of the susceptible larvae. Tobacco budworm P-gp was glycosylated and localized primarily in the cuticle and fat body with little expression in the mid gut. To determine the role of P-gp in pesticide resistance, resistant tobacco budworm larvae were treated with a P-gp inhibitor, quinidine, and challenged with various doses of thiodicarb. Inhibition of P-gp decreased the LD50 for thiodicarb by a factor of 12.5. Quinidine treatment did not result in a significant inhibition of the P-450 system nor did it alter the feeding of the larvae, suggesting the potential involvement of P-gp in pesticide resistance. An age-dependent increase in P-gp expression was detected in resistant larvae as compared to control, susceptible larvae. This correlates with the reported age-dependent increase in resistance and is further evidence supporting the role of P-gp in the development of pesticide resistance.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Anisoles; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Drug Resistance, Multiple; Enzyme Inhibitors; Glycosylation; Insecticides; Larva; Lepidoptera; Lethal Dose 50; Molecular Weight; Piperonyl Butoxide; Quinidine; Quinine; Thiocarbamates; Vinblastine
PubMed: 8898877
DOI: 10.1016/0304-4165(96)00060-8