Multidrug transporters in prokaryotic and eukaryotic cells: physiological functions and transport mechanisms

Blackmore, Colin G.; McNaughton, Peter A.; Veen, Hendrik W van

doi:10.1080/09687680120426

Cited by 19 publications

(25 citation statements)

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“…With remarkably broad substrate recognition, P-gp drives the ATP-dependent efflux of toxic metabolites and xenobiotics from the cell (1) and is thus a central mediator of drug bioavailability. Importantly, P-gp overexpression following drug treatment is responsible for the multidrug resistance (MDR) phenotype, a major reason for chemotherapy failure not only in cancer cells (2) but also in pathogenic microorganisms (3,4). Aside from its well known role in drug efflux, P-gp is also expressed at basal levels in many different tissues, yet the normal physiological functions of the protein remain poorly understood.…”

Section: P-glycoprotein (P-gp Abcb1 Mdr1)mentioning

confidence: 99%

Host Cell P-glycoprotein Is Essential for Cholesterol Uptake and Replication of Toxoplasma gondii

Bottová

Hehl

Štefanić

et al. 2009

Journal of Biological Chemistry

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P-glycoprotein (P-gp) is a membrane-bound efflux pump that actively exports a wide range of compounds from the cell and is associated with the phenomenon of multidrug resistance. However, the role of P-gp in normal physiological processes remains elusive. Using P-gp-deficient fibroblasts, we showed that P-gp was critical for the replication of the intracellular parasite Toxoplasma gondii but was not involved in invasion of host cells by the parasite. Importantly, we found that the protein participated in the transport of host-derived cholesterol to the intracellular parasite. T. gondii replication in P-gp-deficient host cells not only resulted in reduced cholesterol content in the parasite but also altered its sphingolipid metabolism. In addition, we found that different levels of P-gp expression modified the cholesterol metabolism in uninfected fibroblasts. Collectively our findings reveal a key and previously undocumented role of P-gp in hostparasite interaction and suggest a physiological role for P-gp in cholesterol trafficking in mammalian cells.2 is one of the most intensively studied members of the ABC transporter superfamily. With remarkably broad substrate recognition, P-gp drives the ATP-dependent efflux of toxic metabolites and xenobiotics from the cell (1) and is thus a central mediator of drug bioavailability. Importantly, P-gp overexpression following drug treatment is responsible for the multidrug resistance (MDR) phenotype, a major reason for chemotherapy failure not only in cancer cells (2) but also in pathogenic microorganisms (3, 4). Aside from its well known role in drug efflux, P-gp is also expressed at basal levels in many different tissues, yet the normal physiological functions of the protein remain poorly understood.The possibility that physiological levels of host P-gp play a role in host-pathogen interaction, other than mediating drug resistance, has not been investigated so far. We addressed this question using Toxoplasma gondii as a model pathogenic parasite. T. gondii is the causative agent of toxoplasmosis, a potentially fatal disease not only for immunocompromised patients and fetuses but according to recent insights also emerging as a life threatening infection in immunocompetent individuals (5). T. gondii infects virtually all nucleated host cells and resides in a highly specialized vacuole, called the parasitophorous vacuole (PV), which is formed by invaginating the host cell membrane at the time of invasion. The PV is not competent for lysosome fusion, thus avoiding acidification (6), but it is closely associated with host organelles, including lysosomes, mitochondria, and endoplasmic reticulum (reviewed in Ref. 7). Even though the PV does not intersect directly with host vesicular traffic, T. gondii remains dependent on host cells for a number of critical nutrients. Significant progress has been made in our understanding of the mechanisms T. gondii uses to scavenge nutrients from its host, especially in the case of lipid molecules. An important recent example was the identifi...

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Section: P-glycoprotein (P-gp Abcb1 Mdr1)mentioning

confidence: 99%

Host Cell P-glycoprotein Is Essential for Cholesterol Uptake and Replication of Toxoplasma gondii

Bottová

Hehl

Štefanić

et al. 2009

Journal of Biological Chemistry

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“…The analysis of genome sequences has shown that many bacteria appear to have multiple, putative efflux pumps [6,7,8]. The activity of these pumps contributes to the high levels of antibiotic resistance exhibited by organisms such as Pseudomonas aeruginosa [9].…”

Section: Efflux Pumpsmentioning

confidence: 99%

“…Many organisms also possess multidrug transporters that are capable of expelling a wide spectrum of structurally unrelated drugs from prokaryotic cells. Some multidrug resistance pumps, such as the Lmr ATP-dependent ABC transporter from gram-positive bacteria, are homologous to efflux pumps that inhibit the action of chemotherapeutic agents in eukaryotic cells [6]. It has been proposed that these efflux pumps act as "hydrophobic vacuum cleaners" by pumping non-polar compounds from the membrane to the exterior of the cell [10].…”

Section: Efflux Pumpsmentioning

confidence: 99%

Why are bacteria refractory to antimicrobials?

Hogan

Kolter

2002

Current Opinion in Microbiology

142

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“…PGP is considered to play an important role in reducing the absorption of potentially toxic xenobiotics such as those present in the gut lumen either as a result of microbial action in the gut or by ingestion, e.g., in food (Blackmore et al, 2001). With regard to the small intestine, the jejunum has a relatively short transit time (e.g., Ϸ40 min in the rat; Kayne et al, 1993), favoring absorption of lipophilic xenobiotics with high membrane permeability.…”

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confidence: 99%

Region-Dependent Modulation of Intestinal Permeability by Drug Efflux Transporters: In Vitro Studies in mdr1a(−/−) Mouse Intestine

Stephens

Tanianis-Hughes

Higgs

et al. 2002

J Pharmacol Exp Ther

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Information on the extent to which xenobiotics interact with P-glycoprotein (PGP) during transit through the intestine is crucial in determining the influence of PGP on oral drug absorption. We have recently described a novel use of isolated ileum from PGP-deficient mdr1a(Ϫ/Ϫ) mice to resolve PGPand non-PGP-dependent drug efflux and provide a definitive measure of intrinsic drug permeability without recourse to inhibitors (Stephens et al., 2002). The present study uses this approach to investigate the impact of PGP on intestinal permeability of paclitaxel and digoxin in different regions of the mouse intestine (jejunum, ileum, and proximal and distal colon). Absorption of paclitaxel and digoxin in tissues from wild-type mice was low and showed little regional variation. In contrast, absorption of both drugs was markedly higher in mdr1a(Ϫ/Ϫ) intestine, although the increase was highly region-dependent, with the ileum and distal colon showing the greatest effect and much smaller changes in the jejunum and proximal colon. These effects were accompanied by the abolition of paclitaxel and digoxin secretion in mdr1a(Ϫ/Ϫ) mice, suggesting that regional variations in intestinal permeability are masked by differential PGP expression, confirmed by immunoblotting studies. Propranolol permeability, which is not influenced by PGP, showed similar regional variation in both wild-type and mdr1a(Ϫ/Ϫ) tissues, suggesting that differences are at the level of transcellular permeability. These data suggest that the ileum and the distal colon are regions of relatively high transcellular permeability for xenobiotics that are compensated by enhanced expression of PGP.

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Multidrug transporters in prokaryotic and eukaryotic cells: physiological functions and transport mechanisms

Cited by 19 publications

References 0 publications

Host Cell P-glycoprotein Is Essential for Cholesterol Uptake and Replication of Toxoplasma gondii

Host Cell P-glycoprotein Is Essential for Cholesterol Uptake and Replication of Toxoplasma gondii

Why are bacteria refractory to antimicrobials?

Region-Dependent Modulation of Intestinal Permeability by Drug Efflux Transporters: In Vitro Studies in mdr1a(−/−) Mouse Intestine

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