Cholesterol Interaction with the Daunorubicin Binding Site of P-Glycoprotein

Wang, Er-jia; Casciano, Christopher N.; Clement, Robert P.; Johnson, William W.

doi:10.1006/bbrc.2000.3554

Cited by 54 publications

(39 citation statements)

References 55 publications

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“…ABCB1 is the only ABC transporter where the effect of cholesterol on transporter activity has been investigated in detail (Garrigues et al, 2002). Likewise, to our observations (data not shown), most studies have reported an elevation of basal ABCB1 ATPase activity (Wang et al, 2000;Garrigues et al, 2002;Gayet et al, 2005). One study has attributed this increase in ABCB1 ATPase activity to ABCB1-mediated cholesterol flipping (Garrigues et al, 2002).…”

Section: Discussionsupporting

confidence: 86%

“…One study has attributed this increase in ABCB1 ATPase activity to ABCB1-mediated cholesterol flipping (Garrigues et al, 2002). In some studies, cholesterol depletion resulted in an increased stimulation of ABCB1 ATPase activity upon substrate treatment (Garrigues et al, 2002) or increased transport rate (Wang et al, 2000;Gayet et al, 2005). It has been suggested that cholesterol is an ABCB1 substrate, a conclusion challenged lately (Le Goff et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2

Pál¹,

Méhn²,

Molnár³

et al. 2007

J Pharmacol Exp Ther

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ABCG2, a transporter of the ATP-binding cassette family, is known to play a prominent role in the absorption, distribution, metabolism, and excretion of xenobiotics. Drug-transporter interactions are commonly screened by high-throughput systems using transfected insect and/or human cell lines. The determination of ABCG2-ATPase activity is one method to identify ABCG2 substrate and inhibitors. We demonstrate that the ATPase activities of the human ABCG2 transfected Sf9 cell membranes (MXR-Sf9) and ABCG2-overexpressing human cell membranes (MXR-M) differ. Variation due to disparity in the glycosylation level of the protein had no effect on the transporter. The influence of cholesterol on ABCG2-ATPase activity was investigated because the lipid compositions of insect and human cells are largely different from each other. Differences in cholesterol content, shown by cholesterol loading and depletion experiments, conferred the difference in stimulation of basal ABCG2-ATPase of the two cell membranes. Basal ABCG2-ATPase activity could be stimulated by sulfasalazine, prazosin, and topotecan, known substrates of ABCG2 in cholesterol-loaded MXR-Sf9 and MXR-M cell membranes. In contrast, ABCG2-ATPase could not be stimulated in MXR-Sf9 or in cholesterol-depleted MXR-M membranes. Moreover, cholesterol loading significantly improved the drug transport into inside-out membrane vesicles prepared from MXR-Sf9 cells. MXR-M and cholesterol-loaded MXR-Sf9 cell membranes displayed similar ABCG2-ATPase activity and vesicular transport. Our study indicates an essential role of membrane cholesterol for the function of ABCG2.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2

Pál¹,

Méhn²,

Molnár³

et al. 2007

J Pharmacol Exp Ther

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“…However, the possibility of an interaction between the first cytolosic loops (CL1) of two neighboring Pdr5p molecules has been reported recently and could possibly have implications for dimerization of this ABC transporter (56). In addition, a dimeric organization of different ABC transporters in native membranes has been proposed based on radiation inactivation and cross-linking experiments, as well as on the use of fusion proteins or monoclonal antibodies (57)(58)(59)(60)(61).…”

Section: Resultsmentioning

confidence: 99%

Three-dimensional Reconstruction of the Saccharomyces cerevisiae Multidrug Resistance Protein Pdr5p

Ferreira‐Pereira¹,

Marco

Decottignies³

et al. 2003

Journal of Biological Chemistry

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“…The Pgp in the human adrenals may therefore either be accidental or reflect the exposure of primates to toxins especially deleterious to the adrenal cortex. Whether cholesterol, the major sterol in mammalian membrane, is translocated by Pgp (156,157) is doubtful in our opinion and requires confirmation by direct transport experiments, as pointed out by Johnstone et al (151). This also holds for the postulated role of Pgp in cholesterol esterification (158,159).…”

mentioning

confidence: 84%

Mammalian ABC Transporters in Health and Disease

Borst

Elferink

2002

Annu. Rev. Biochem.

1,413

1,152

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f Abstract The ATP-binding cassette (ABC) transporters are a family of large proteins in membranes and are able to transport a variety of compounds through membranes against steep concentration gradients at the cost of ATP hydrolysis. The available outline of the human genome contains 48 ABC genes; 16 of these have a known function and 14 are associated with a defined human disease. Major physiological functions of ABC transporters include the transport of lipids, bile salts, toxic compounds, and peptides for antigen presentation or other purposes. We review the functions of mammalian ABC transporters, emphasizing biochemical mechanisms and genetic defects. Our overview illustrates the importance of ABC transporters in human physiology, toxicology, pharmacology, and disease. We focus on three topics: (a) ABC transporters transporting drugs (xenotoxins) and drug conjugates. (b) Mammalian secretory epithelia using ABC transporters to excrete a large number of substances, sometimes against a steep concentration gradient. Several inborn errors in liver metabolism are due to mutations in one of the genes for these pumps; these are discussed. (c) A rapidly increasing number of ABC transporters are found to play a role in lipid transport. Defects in each of these transporters are involved in human inborn or acquired diseases.

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Cholesterol Interaction with the Daunorubicin Binding Site of P-Glycoprotein

Cited by 54 publications

References 55 publications

Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2

Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2

Three-dimensional Reconstruction of the Saccharomyces cerevisiae Multidrug Resistance Protein Pdr5p

Mammalian ABC Transporters in Health and Disease

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