Polymorphic Expression of Multidrug Resistance mRNA in Lung Parenchyma of Nonpregnant and Pregnant Rats: A Comparison to Cystic Fibrosis mRNA Expression

Johannesson, Marie; Nordqvist, Ann‐Christin Sandberg; Bogdanović, Nenad; Hjelte, Lena; Schalling, Martin

doi:10.1006/bbrc.1997.7519

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…Previous studies that have commented upon P-gp expression within the alveolar region are limited with a lack of definitive investigations examining the alveolar epithelium specifically. Using an in situ hybridization technique with probes against mdr-1b, Johannesson et al (1997) noted positive staining in rat lung parenchyma, although they were unable to identify the cell type expressing the mdr-1b transcript. Using RT-PCR analysis of primary cultures of human lung epithelial cells (separated on the basis of size into ciliated epithelial cells Ͼ40 m and alveolar epithelial cells Ͻ40 m), Bagru et al (1998) reported the presence of P-gp transcript in primary 7 day cultures of the Ͻ40-m cell population.…”

Section: Discussionmentioning

confidence: 99%

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

Campbell¹,

Abulrob²,

Kandalaft³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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The multidrug resistant (MDR) transporter P-glycoprotein (Pgp) is constitutively expressed in normal tissues, where its spatial distribution defines it as an important element reducing the systemic exposure and tissue access of potentially harmful xenobiotics. We sought to determine whether P-gp is functionally expressed within alveolar epithelium of lung, in particular within the predominant cell type of this barrier, the alveolar epithelial (AE) type I cell. By immunohistochemistry, MDR-1/ mdr-1 P-gp was localized to luminal membranes of AE type I epithelium within normal human and rat lung tissue. Using a primary rat cell culture model affording study of AE type II to AE type I differentiation, we observed increased expression (reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and immunoflow cytometry techniques) of mdr-1a and mdr-1b P-gp in the cultures as they adopted an AE type I phenotype; freshly isolated AE type II cells were negative for mdr-1/P-gp. The functionality of P-gp within the AE cultures was demonstrated by a flow cytometric accumulation-retention assay using rhodamine-123 as substrate, and also by the polarized transport of vinblastine across confluent AE type I monolayers (basal-to-apical permeability was 3-fold that of apical-to-basal permeability), which was found to be comparable with the P-gp transport barrier presented by Caco-2 cell monolayers. The implications of localizing P-gp within alveolar epithelium is of significance to studies of fundamental respiratory cell biology as well as to further clarifying the nature of the barrier to xenobiotic transfer from alveolar airspace to pulmonary interstitium and capillary blood.P-Glycoprotein (P-gp) is a member of the ATP-binding cassette superfamily of membrane transport proteins that mediates the vectorial movement across cell membranes of a wide range of physicochemically diverse solutes (Stouch and Gudmundsson, 2002). In humans, two P-gp-related genes have been cloned and subsequently termed MDR1 and MDR3 (for review, see Ambudkar et al., 1999). The MDR1/P-gp gene product is recognized in particular to actively efflux from a cell a diverse range of cytotoxic drugs, a characteristic that is an important facet in the multidrug resistant (MDR) cell phenotype. Current evidence suggests that the MDR3/P-gp gene product does not contribute to an MDR phenotype.In rodents, three P-gp-related genes have been identified and designated mdr-1a, mdr-1b, and mdr-

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Section: Discussionmentioning

confidence: 99%

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

Campbell¹,

Abulrob²,

Kandalaft³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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“…There is precedence for this statement in that coordinate regulation between expression of cftr and mdr1 has been reported to occur across several species (29)(30)(31). A recent study by Trezise et al, 1997 (29) suggests that expression of transporters like mdr1 (multidrug resistance) may be coordinately regulated with ctfr expression.…”

Section: Discussionmentioning

confidence: 99%

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

2000

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Drug treatment poses a therapeutic challenge in cystic fibrosis (CF) because the disposition of a number of drugs is altered in CF. Enhanced clearance of acetaminophen (APAP) and indocyanine green (ICG) have previously been reported in CF patients. The objective of the current study was to investigate if the CF-knockout mouse model (cftr m1UNC ) shows altered pharmacokinetics similar to those seen in CF patients using the 2 model compounds APAP and ICG. Clearance (CL/F) of APAP and renal (CL R ) and formation (CL f ) clearance of acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) were determined in CFknockout mice following administration of APAP (50 mg/kg, intraperitoneal). CL R of AS was 19.5 and 12.9 (mL/min per kg) and CL f of AS was 10.4 and 6.7 mL/min per kg for homozygous and heterozygous males, respectively, which was significantly different between groups. CL R of AG was 6.3 and 4.8 mL/min per kg and CL f of AG was 9.6 and 8.9 mL/min per kg for homozygous and heterozygous males, respectively, although not reaching statistical significance. No significant differences were noted in either Cl R or CL f of AG and AS in female CF mice. Plasma concentrations of ICG (10 mg/kg, intravenous) were determined over 0 to 15 minutes. Homozygous females showed a higher apparent volume of distribution (96 mL/kg) relative to heterozygous females (72 mL/kg). Similar to CF

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“…MDR has been shown to regulate volume-activated chloride channel activity [38][39][40]. In a study on rats, two subsets were found, expressing high and low MDR protein levels in lung tissue [41]. Hence differential expression of MDR between patients might influence chloride efflux characterization.…”

Section: Figure 3 Differences In Chloride Efflux Between Repeated Meamentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes

Andersson

Dragomir

Hjelte³

et al. 2002

Clinical Science

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Cystic fibrosis is a heterogenic disease, in which the phenotype can also vary for patients with the same genotype. In the present study the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in nasal epithelial cells from 19 adult patients with cystic fibrosis was investigated. All patients had severe mutations, whereby no or little functional CFTR is expected in the plasma membrane. Of the patients, 15 were homozygous for deltaF508-CFTR (i.e. CTFR lacking residue Phe-508). The others were deltaF508-heterozygous with 3659delC, 394delTT or 2183AA-->G. Nasal epithelial cells, obtained by nasal brushings, were loaded with the fluorescent probe N -(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide to measure Cl(-) efflux. In most of the cystic fibrosis patients, forskolin plus isobutylmethylxanthine was unable to elicit any response. Unexpectedly, cells from three cystic fibrosis patients (two deltaF508/deltaF508 patients and one deltaF508/3659delC patient) responded to stimulation in a wild-type manner. It was investigated whether this residual chloride transport function was associated with a milder phenotype. Clinical parameters studied were lung function, number of antibiotic courses, Shwachman score, Bhalla score, age at chronic colonization with Pseudomonas aeruginosa and the pattern of essential fatty acids in serum phospholipids. Unknown factors may affect the presence of functional CFTR in patients with severe CFTR mutations. However, we could not find a correlation between the response to cAMP and any of the phenotype parameters. It appears that functional cAMP transport in the nasal epithelium is no guarantee of a mild phenotype and, conversely, that a patient lacking cAMP-dependent chloride transport can develop a mild phenotype.

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Polymorphic Expression of Multidrug Resistance mRNA in Lung Parenchyma of Nonpregnant and Pregnant Rats: A Comparison to Cystic Fibrosis mRNA Expression

Cited by 9 publications

References 34 publications

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

Constitutive Expression of P-Glycoprotein in Normal Lung Alveolar Epithelium and Functionality in Primary Alveolar Epithelial Cultures

Disposition of acetaminophen and indocyanine green in cystic fibrosis-knockout mice

Cystic fibrosis transmembrane conductance regulator (CFTR) activity in nasal epithelial cells from cystic fibrosis patients with severe genotypes

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