Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease

Smit, Jan Maerten; Schinkel, Alfred H.; Elferink, Ronald P.J. Oude; Groen, Albert K.; Wagenaar, Els; Deemter, Liesbeth van; Mol, C. A. A. M.; Ottenhoff, R.; Lugt, N. M. T. Van Der; Roon, Marian A. van; Valk, Martin A. van der; Offerhaus, G. J. A.; Berns, Anton; Borst, Piet

doi:10.1016/0092-8674(93)90380-9

Cited by 1,389 publications

(1,018 citation statements)

References 68 publications

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“…Transfecting polarized cells with ABCB4 increases the rate of transport of fluorescent labeled PC, but not other phospholipids, such as phosphatidylethanolamine 2,8,9 . The histologic pattern of PFIC type 3 is very similar to the MDR 2 knockout mouse 7 . Interestingly, abcb4 knockout mice also demonstrate decreased cholesterol excretion, proof that PC in mixed micelles is necessary to allow adequate biliary excretion of cholesterol.…”

Section: Physiology and Regulationmentioning

confidence: 78%

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The multiple facets of ABCB4 (MDR3) deficiency

Sundaram

Sokol²

2007

Curr Treat Options Gastro

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Section: Physiology and Regulationmentioning

confidence: 78%

“…In PFIC 3, UDCA may alter biliary bile acid composition in favor of hydrophilic bile acids, which are less toxic to the bile duct epithelium 7,21 . Jacquemin et al found that 46% of patients with PFIC type 3 responded completely to UDCA (20-30 mg/kg/day divided BID), with normalization of liver function tests.…”

Section: Treatmentmentioning

confidence: 99%

The multiple facets of ABCB4 (MDR3) deficiency

Sundaram

Sokol²

2007

Curr Treat Options Gastro

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“…It was shown that phosphatidylcholine is transported by the MDR2-encoded P-glycoprotein (Smit et al, 1993;Ruetz et al, 1994). Because ilmofosine is a phosphatidylcholine analogue, it could be speculated that MDR2 is responsible for differences in the sensitivity to the compound.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported recently that the MDR2-encoded P-glycoprotein transports phosphatidylcholine out of the cell (Smit et al, 1993;Ruetz et al, 1994). For this reason, we investigated whether this gene is involved in the resistance to ilmofosine by detection of the MDRJ and MDR2 mRNA levels.…”

Section: Expression Of the Mdr2 Genementioning

confidence: 98%

“…Recently, it was reported that the MDR2-encoded P-glycoprotein has an essential role in the translocation of phosphatidylcholine (Smit et al, 1993;Ruetz et al, 1994). Ilmofosine is a phosphatidylcholine analogue in which the long chain alkyl group is linked by a thioether bond and the f-hydroxyl group of the glycerol has been replaced by a methoxymethyl moiety.…”

mentioning

confidence: 99%

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Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440)

Hofmann

Utz²,

Spitaler³

et al. 1997

Br J Cancer

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Summary The thioether phospholipid ilmofosine (BM 41 440) is a new anti-cancer drug presently undergoing phase 11 clinical trials. Because resistance to anti-tumour drugs is a major problem in cancer treatment, we investigated the resistance of different cell lines to this compound.Here we report that the multidrug-resistant cell lines MCF7/ADR, CCRFNCR1000, CCRF/ADR500, CEMNLB100 and HeLa cell lines transfected with a wild-type and mutated (gly/vall 85) multidrug resistance 1 gene (MDR1) are cross-resistant to ilmofosine compared with the sensitive parental cell lines. In CEMNM-1 cells, in which the resistance is associated with an altered topoisomerase 11 gene, no crossresistance to ilmofosine was observed. Ilmofosine is not capable of modulating multidrug resistance and neither does it reduce the labelling of the P-glycoprotein (P-gp) by azidopine nor alter ATPase activity significantly. The resistance to ilmofosine in multidrug-resistant CCRFNCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035). A tenfold excess of ilmofosine does not prevent the MDR-modulating effect of dexniguldipine-HCI. Treatment of cells with ilmofosine does not alter the levels of MDR1 mRNA. Long-term treatment of an ilmofosine-resistant Meth A subline with the drug does not induce multidrug resistance, indicating that ilmofosine does not increase the level of P-gp. Determination of the MDR2 mRNA levels in the cells revealed that the resistance pattern to ilmofosine is not correlated with the expression of this gene. It is concluded, therefore, that multidrug-resistant cells are cross-resistant to ilmofosine and that the compound is not a substrate of Pgp. No association between the expression of the MDR2-encoded P-gp and resistance to ilmofosine was observed. It is supposed that MDR1-associated alterations in membrane lipids cause resistance to ilmofosine.

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Adventures With Parasites, Metabolism, Inborn Errors, and Cancer

Borst

2023

JAMA

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Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease

Cited by 1,389 publications

References 68 publications

The multiple facets of ABCB4 (MDR3) deficiency

The multiple facets of ABCB4 (MDR3) deficiency

Resistance to the new anti-cancer phospholipid ilmofosine (BM 41 440)

Adventures With Parasites, Metabolism, Inborn Errors, and Cancer

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