Multidrug Resistance P-Glycoprotein Is Not Involved in Cholesterol Esterification

Issandou, Marc; Grand-Perret, Thierry

doi:10.1006/bbrc.2000.3939

Cited by 15 publications

(12 citation statements)

References 54 publications

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“…For example, verapamil, a nonspecific P-gp inhibitor, was found to inhibit cellular cholesterol esterification (4,5), and P-gp-transfected NIH 3T3 fibroblasts grown under drug selection were also found to have increased cholesterol esterification, without an increase in plasma membrane cholesterol content (5). However, another report, although repeating the verapamil effect, failed to find any effect of a specific P-gp inhibitor, GF120981, on the esterification of lipoproteinderived cholesterol in HepG2 cells (17). Our study in a Pgp-inducible cell line also failed to find any effect of P-gp expression on cellular cholesterol esterification or on the mass ratio of cellular CE to FC.…”

Section: Discussioncontrasting

confidence: 66%

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis

Goff

Settle

Greene

et al. 2006

Journal of Lipid Research

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The multidrug resistance P-glycoprotein (P-gp) was recently proposed to redistribute cholesterol in the plasma membrane, suggesting that P-gp could modulate cholesterol efflux to cholesterol acceptors. To address this hypothesis and to reevaluate the role of P-gp in cholesterol homeostasis, we first analyzed the role of P-gp expression on cholesterol efflux in P-gp stably transfected drug-selected LLC-MDR1 cells. Cholesterol efflux to methyl-b-cyclodextrin (CD) was 4-fold higher in LLC-MDR1 cells compared with control LLC-PK1 cells, indicating that the accessible pool of plasma membrane cholesterol was increased by P-gp expression. However, using the P-gp-inducible cells lines HeLa MDR-Tet and 77.1 MDR-Tet, cholesterol efflux to CD, apolipoprotein A-I, or HDL was not associated with P-gp expression. In addition, we did not observe any effect of Pgp expression on cellular free and esterified cholesterol content, cholesteryl ester uptake from LDL and HDL particles, or acyl-CoA:cholesterol acyltransferase activity. Therefore, we conclude that P-gp expression does not play a major role in cholesterol homeostasis in P-gp-inducible cells and that the effects of P-gp on cholesterol homeostasis previously described in drug-selected cells might result from non-P-gp pathways that were also induced by selection for drug resistance.-Le Goff, W., M. Settle, D. J. Greene, R. E. Morton, and J. D. Smith. Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis. J. Lipid Res. 2006. 47: 51-58. Supplementary key words cholesterol efflux . ABCA1 . cyclodextrin . apolipoprotein A-I P-glycoprotein (P-gp) is a member of the ATP binding cassette transporter family responsible for the multidrug resistance (MDR) phenotype. P-gp is the protein product of the human MDR1 gene (ABCB1 is the official gene symbol), and P-gp is highly expressed in the intestine, liver, kidney, placenta, and the blood-brain barrier. Plasma membrane P-gp mediates the efflux of numerous neutral and cationic organic compounds and drugs, among them chemotherapeutic drugs, thereby contributing to the MDR phenotype in many cancers. However, information concerning endogenous substrates for P-gp as well as the physiological role of P-gp is still lacking (1).P-gp has been reported to modulate cellular cholesterol homeostasis via several mechanisms. Stable transfection of a rat intestinal cell line with a P-gp expression vector led to a modest increase in the uptake of cholesterol-containing micelles (2). Nonspecific P-gp inhibitors have been reported to inhibit cholesterol biosynthesis in CHO-7 cells (3) and to inhibit cellular cholesterol esterification (4). Transfection of NIH 3T3 cells with a P-gp expression vector followed by selection for drug resistance was associated with increased esterification of plasma membrane cholesterol (5). Mice, unlike humans, have two copies of the gene for P-gp, abcb1a and abcb1b (previously mdr1a and mdr1b). Mice deficient in both of these genes have been constructed, and althou...

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Section: Discussioncontrasting

confidence: 66%

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis

Goff

Settle

Greene

et al. 2006

Journal of Lipid Research

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“…Therefore, the availability of a cholesterol substrate in the ER, which is the major determinant of ACAT activity, may be regulated by both P-gp and caveolin-1 (37). These findings would explain the lack of correlation between P-gp activity and intracellular cholesterol esterification found in HepG2 cells (38).…”

Section: Discussionmentioning

confidence: 98%

High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent

Rodrigues

Rebecchi

Bertolami

et al. 2005

Braz J Med Biol Res

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The MDR1 gene encodes the P-glycoprotein, an efflux transporter with broad substrate specificity. P-glycoprotein has raised great interest in pharmacogenetics because it transports a variety of structurally divergent drugs, including lipid-lowering drugs. The synonymous single-nucleotide polymorphism C3435T and the nonsynonymous single-nucleotide polymorphism G2677T/A in MDR1 have been indicated as potential determinants of variability in drug disposition and efficacy. In order to evaluate the effect of G2677T/A and C3435T MDR1 polymorphisms on serum levels of lipids before and after atorvastatin administration, 69 unrelated hypercholesterolemic individuals from São Paulo city, Brazil, were selected and treated with 10 mg atorvastatin orally once daily for four weeks. MDR1 polymorphisms were analyzed by PCR-RFLP. C3435T and G2677T polymorphisms were found to be linked. The allelic frequencies for C3435T polymorphism were 0.536 and 0.464 for the 3435C and 3435T alleles, respectively, while for G2677T/A polymorphism allele frequencies were 0.580 for the 2677G allele, 0.384 for the 2677T allele and 0.036 for the 2677A allele. There was no significant relation between atorvastatin response and MDR1 polymorphisms (repeated measures ANOVA; P > 0.05). However, haplotype analysis revealed an association between T/T carriers and higher basal serum total (TC) and LDL cholesterol levels (TC: 303 ± 56, LDL-C: 216 ± 57 mg/dl, respectively) compared with non-T/T carriers (TC: 278 ± 28, LDL-C: 189 ± 24 mg/dl; repeated measures ANOVA/Tukey test; P < 0.05). These data indicate that MDR1 polymorphism may have an important contribution to the control of basal serum cholesterol levels in Brazilian hypercholesterolemic individuals of European descent.

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“…Also, when comparing KB MDR cells with sensitive cells, there was no correlation observed between modulation of P-gp-mediated drug transport and inhibition of cholesterol esterification [140]. Accordingly, the P-gp inhibitor GF120918 inhibited cholesterol esterification neither in HepG2 nor in MDR MCF-7/ADR cells [141]. However, the in vivo consequences of the possible role of P-gp on cholesterol traffic observed in cultured cells are still unclear.…”

Section: P-gp Participates In Cholesterol Cellular Traffic and Metabomentioning

confidence: 98%

P-glycoprotein and ‘lipid rafts’: some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)

Orlowski

Martin

Escargueil

2006

Cell. Mol. Life Sci.

113

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P-glycoprotein (P-gp) is an active membrane transporter responsible for cell detoxification against numerous amphiphilic compounds, leading to multidrug resistance in tumor cells. It displays entangled connections with its membrane environment since it recognizes its substrates within the cytosolic leaflet and it also translocates some endogenous lipids to the exoplasmic leaflet. Regarding its relationships with membrane microdomains, 'lipid rafts', a literature analysis concludes that (i) P-gp also exists in rafts and non-raft membrane domains, depending on the cell considered, the experimental conditions and the method used to test it; (ii) cholesterol has a positive influence on P-gp function, and this may be a direct effect of the free cholesterol present in membrane or an indirect effect mediated by the cholesterol-enriched microdomains; (iii) when present in rafts, P-gp interacts with protein partners regulating its activity; (iv) P-gp is a lipid translocase that handles the raft-constituting lipids with particular efficiency, and it also influences membrane trafficking in the cell.

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Multidrug Resistance P-Glycoprotein Is Not Involved in Cholesterol Esterification

Cited by 15 publications

References 54 publications

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis

High baseline serum total and LDL cholesterol levels are associated with MDR1 haplotypes in Brazilian hypercholesterolemic individuals of European descent

P-glycoprotein and ‘lipid rafts’: some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)

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