Control Analysis of Biliary Lipid Secretion

Groen, Albert K.; Elferink, Ronald P.J. Oude; Tager, J. M.

doi:10.1006/jtbi.1996.0183

Cited by 17 publications

(10 citation statements)

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“…These results strongly suggest that the activity of mdr2 Pgp is a ratecontrolling step in the secretion of phospholipids. Quantitative analysis of lipid secretion in the different mouse genotypes confirmed this contention [5]. We have previously hypothesized that mdr2 Pgp transports phospholipids from the inner leaflet to the outer leaflet of the canalicular membrane, and that the interaction of bile salts with the outer leaflet of the membrane leads to the secretion of phospholipids into canalicular bile [4,6].…”

Section: Introductionmentioning

confidence: 62%

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Regulation of MDR2 P-glycoprotein expression by bile salts

et al. 1995

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Section: Introductionmentioning

confidence: 62%

“…We have shown previously that mdr2 Pgp activity is a rate-controlling step in the secretion of phospholipids into bile [5]. Therefore phospholipid secretion reflects the functional level of canalicular-localized mdr2 Pgp.…”

Section: % (W/w) Cholatementioning

confidence: 85%

Regulation of MDR2 P-glycoprotein expression by bile salts

et al. 1995

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“…Within individual liver grafts, mRNA levels of MDR3, ABCG5, and ABCG8 did not change very much. Because phospholipids may drive cholesterol secretion and MDR3 controls phospholipid output, 30,31 relationships between levels of hepatic expression of ABCG5 and ABCG8 to MDR3 were analyzed. At all 3 time points, strong positive correlations were found between levels of ABCG5/MDR3 and ABCG8/MDR3 expression ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Hepatic expression of ABC transporters G5 and G8 does not correlate with biliary cholesterol secretion in liver transplant patients

et al. 2005

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The adenosine triphosphate (ATP)-binding cassette (ABC)-transporters ABCG5 and ABCG8 have been shown to mediate hepatic and intestinal excretion of cholesterol. In various (genetically modified) murine models, a strong relationship was found between hepatic expression of ABCG5/ABCG8 and biliary cholesterol content. Our study aimed to relate levels of hepatic expression of ABCG5 and ABCG8 to biliary excretion of cholesterol in man. From 24 patients who had received a liver transplant, bile samples were collected daily after transplantation over a 2-week period to determine biliary composition. Expression of ABCG5, ABCG8, MDR3, and BSEP was assessed by real-time polymerase chain reaction (PCR) in liver biopsy specimens collected before and after transplantation. Levels of hepatic ABCG5, ABCG8, and MDR3 messenger RNA (mRNA) were strongly correlated. After transplantation, the biliary secretion rate of cholesterol continuously increased, coinciding with gradual increases in bile salt and phospholipid secretion. In contrast, hepatic levels of ABCG5 and ABCG8 mRNA remained unchanged. Surprisingly, no correlation was found between the hepatic expression of ABCG5 and ABCG8 and rates of biliary cholesterol secretion, normalized for biliary phospholipid secretion. As expected, the concentration of biliary phospholipids correlated well with MDR3 expression. In conclusion, the strong relationship between ABCG5 and ABCG8 gene expression is consistent with the coordinate regulation of both genes, and in line with heterodimerization of both proteins into a functional transporter. Hepatic ABCG5/ABCG8 expression, at least during the early phase after transplantation, is not directly related to biliary cholesterol secretion in humans. This finding suggests the existence of alternative pathways for the hepatobiliary transport of cholesterol that are not controlled by ABCG5/ABCG8. (HEPATOLOGY 2005;42:1166-1174

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“…Mayer et al (45) have shown that PSC 833 has no effect at all on secretion of PC into bile at drug concentrations that strongly inhibit the secretion of digoxin or paclitaxel from the liver into bile. Since the MDR3 P-gp concentration has been shown to be a controlling step for PC secretion into bile (18,46), it is unlikely that a partial inhibition by PSC 833 would have been missed in these experiments. The fact that we can readily inhibit C 6 -NBD-PC transport with reversal agents in vitro (Fig.…”

Section: Discussionmentioning

confidence: 99%

MDR3 P-glycoprotein, a Phosphatidylcholine Translocase, Transports Several Cytotoxic Drugs and Directly Interacts with Drugs as Judged by Interference with Nucleotide Trapping

Smith¹,

Helvoort²,

Meer³

et al. 2000

Journal of Biological Chemistry

228

158

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The human MDR3 gene is a member of the multidrug resistance (MDR) gene family. The MDR3 P-glycoprotein is a transmembrane protein that translocates phosphatidylcholine. The MDR1 P-glycoprotein related transports cytotoxic drugs. Its overexpression can make cells resistant to a variety of drugs. Attempts to show that MDR3 P-glycoprotein can cause MDR have been unsuccessful thus far. Here, we report an increased directional transport of several MDR1 P-glycoprotein substrates, such as digoxin, paclitaxel, and vinblastine, through polarized monolayers of MDR3-transfected cells. Transport of other good MDR1 P-glycoprotein substrates, including cyclosporin A and dexamethasone, was not detectably increased. MDR3 P-glycoprotein-dependent transport of a short-chain phosphatidylcholine analog and drugs was inhibited by several MDR reversal agents and other drugs, indicating an interaction between these compounds and MDR3 P-gp. Insect cell membranes from Sf9 cells overexpressing MDR3 showed specific MgATP binding and a vanadate-dependent, Nethylmaleimide-sensitive nucleotide trapping activity, visualized by covalent binding with [␣-32 P]8-azido-ATP. Nucleotide trapping was (nearly) abolished by paclitaxel, vinblastine, and the MDR reversal agents verapamil, cyclosporin A, and PSC 833. We conclude that MDR3 P-glycoprotein can bind and transport a subset of MDR1 P-glycoprotein substrates. The rate of MDR3 Pglycoprotein-mediated transport is low for most drugs, explaining why this protein is not detectably involved in multidrug resistance. It remains possible, however, that drug binding to MDR3 P-glycoprotein could adversely affect phospholipid or toxin secretion under conditions of stress (e.g. in pregnant heterozygotes with one MDR3 null allele). P-glycoproteins (P-gps)1 are 170-kDa glycosylated membrane proteins that actively transport their substrates out of the cell. Two P-gp genes have been identified in humans. The human MDR1 gene encodes a drug transporting P-gp that can actively extrude a range of cytotoxic anticancer drugs from the cytoplasm. Overexpression of this P-gp gene results in a decreased intracellular accumulation of these drugs and renders the cell multidrug resistant (1-3). The second human P-gp gene is MDR3 (also known as MDR2) (4, 5). Attempts to obtain resistance against cytotoxic drugs by transfecting drug-sensitive cell lines with the MDR3 cDNA or its mouse homolog, Mdr2, yielded only negative results (4, 6 -9). Amplification or activation of the MDR3 gene, independent of the closely linked MDR1, has never been found in multidrug-resistant cell lines (10 -12). Nevertheless, two studies suggest a role for MDR3 P-gp in drug transport: 1) analysis of B-cell leukemias showed a correlation between MDR3 overexpression and daunorubicin transport (13, 14), and 2) Kino et al. (15) found low level resistance against the antifungal agent aureobasidin A in yeast transformed with the human MDR3 cDNA.The function of the murine homolog of human MDR3 P-gp, Mdr2 P-gp, became clear when Smit et al. (16,17) generated...

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Control Analysis of Biliary Lipid Secretion

Cited by 17 publications

References 0 publications

Regulation of MDR2 P-glycoprotein expression by bile salts

Regulation of MDR2 P-glycoprotein expression by bile salts

Hepatic expression of ABC transporters G5 and G8 does not correlate with biliary cholesterol secretion in liver transplant patients

MDR3 P-glycoprotein, a Phosphatidylcholine Translocase, Transports Several Cytotoxic Drugs and Directly Interacts with Drugs as Judged by Interference with Nucleotide Trapping

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