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The effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminosilicate (NSAS) on the expression and activity of P-glycoprotein within Caco-2 cells Sachs-Barrable, Kristina; Darlington, Jerald W; Wasan, Kishor M
Abstract
Background: Many drugs are substrates for P-glycoprotein (P-gp) and interactions involving P-gp may be relevant to clinical practice. Co-administration with P-gp inhibitors or inducers changes the absorption profile as well as the risk for drug toxicity, therefore it is important to evaluate possible P-gp alterations. The purpose of this study was to investigate the effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminium silicate (NSAS), a protonated montmorillonite clay, on mdr-1 gene expression and its protein, P-glycoprotein (P-gp) within Caco-2 cells. Methods: The effects of DAPP and NSAS on the regulation of mdr-1 gene, P-gp protein expression and activity within Caco-2 cells, were determined using cell viability and cytotoxicity tests, RT-PCR, Western Blot analysis and bi-directional transport studies. Results: We observed a significant down-regulation of mdr-1 mRNA (e.g. 38.5 ± 17% decrease vs. control at 5 μM DAPP and 61.2 ± 25% versus control at 10 μM DAPP; n = 6, P* < 0.05) within Caco-2 cells. Western Blot analysis of P-gp expression showed that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. This down-regulation of P-glycoprotein also resulted in decreased activity of P-glycoprotein compared to untreated control. In contrast, when Caco-2 cells were treated with NSAS, no changes in mdr-1 gene expression, P-gp protein expression nor P-gp activity were observed. Conclusions: DAPP but not NSAS decreases P-gp mediated drug efflux through decreased mdr-1 gene expression and consequently decreased P-gp protein expression. These findings have to be taken into consideration when DAPP is concurrently given with other drugs that are substrates for P-gp since drug-drug interactions harbour a safety issue and alter bioavailability profiles. NSAS does not have any P-gp altering properties and therefore might not affect drug-drug interactions. We conclude from this study that NSAS might make a safer drug candidate compared to DAPP for lowering LDL-cholesterol.
Item Metadata
Title |
The effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminosilicate (NSAS) on the expression and activity of P-glycoprotein within Caco-2 cells
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Creator | |
Publisher |
BioMed Central
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Date Issued |
2014-10-01
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Description |
Background:
Many drugs are substrates for P-glycoprotein (P-gp) and interactions involving P-gp may be relevant to clinical practice. Co-administration with P-gp inhibitors or inducers changes the absorption profile as well as the risk for drug toxicity, therefore it is important to evaluate possible P-gp alterations. The purpose of this study was to investigate the effect of two novel cholesterol-lowering agents, disodium ascorbyl phytostanol phosphate (DAPP) and nanostructured aluminium silicate (NSAS), a protonated montmorillonite clay, on mdr-1 gene expression and its protein, P-glycoprotein (P-gp) within Caco-2 cells.
Methods:
The effects of DAPP and NSAS on the regulation of mdr-1 gene, P-gp protein expression and activity within Caco-2 cells, were determined using cell viability and cytotoxicity tests, RT-PCR, Western Blot analysis and bi-directional transport studies.
Results:
We observed a significant down-regulation of mdr-1 mRNA (e.g. 38.5 ± 17% decrease vs. control at 5 μM DAPP and 61.2 ± 25% versus control at 10 μM DAPP; n = 6, P* < 0.05) within Caco-2 cells. Western Blot analysis of P-gp expression showed that changes in mdr-1 gene expression lead to correlating changes in P-gp protein expression. This down-regulation of P-glycoprotein also resulted in decreased activity of P-glycoprotein compared to untreated control. In contrast, when Caco-2 cells were treated with NSAS, no changes in mdr-1 gene expression, P-gp protein expression nor P-gp activity were observed.
Conclusions:
DAPP but not NSAS decreases P-gp mediated drug efflux through decreased mdr-1 gene expression and consequently decreased P-gp protein expression. These findings have to be taken into consideration when DAPP is concurrently given with other drugs that are substrates for P-gp since drug-drug interactions harbour a safety issue and alter bioavailability profiles.
NSAS does not have any P-gp altering properties and therefore might not affect drug-drug interactions. We conclude from this study that NSAS might make a safer drug candidate compared to DAPP for lowering LDL-cholesterol.
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Genre | |
Type | |
Language |
eng
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Date Available |
2016-01-19
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution 4.0 International (CC BY 4.0)
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DOI |
10.14288/1.0223758
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URI | |
Affiliation | |
Citation |
Lipids in Health and Disease. 2014 Oct 01;13(1):153
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Publisher DOI |
10.1186/1476-511X-13-153
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Peer Review Status |
Reviewed
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Scholarly Level |
Faculty
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Copyright Holder |
Sachs-Barrable et al.; licensee BioMed Central Ltd.
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution 4.0 International (CC BY 4.0)