Poloxamer 407 (P-407)-mediated Reduction in the Gene Expression of Atp-binding-cassette Transporter A1 May Contribute to Increased Cholesterol in Peripheral Tissues of P-407-treated Rats.
From: Division of Pharmaceutical Science, Rm. 211A, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, Missouri 64110-2499, United States. johnstont@umkc.edu
European journal of pharmacology
- Publish Date: May 2006
- ISSN: 0014-2999
- Volume: 536
- Issue: 3
- Pages: 232-40
- Medium: Print
- Language: English
- Citation (JAMA): Johnston Thomas P, Jaye Michael, Webb Christine L, et al. Poloxamer 407 (P-407)-mediated Reduction in the Gene Expression of Atp-binding-cassette Transporter A1 May Contribute to Increased Cholesterol in Peripheral Tissues of P-407-treated Rats.. Eur. J. Pharmacol. May 2006;536:232-40
Abstract
The purpose of this study was to determine whether poloxamer 407, a chemical known to increase plasma lipid levels in rodents following parenteral administration, decreased the gene expression of ATP-binding-cassette transporter A1. Using human macrophages cultured with poloxamer 407, there was a significant reduction in the gene expression of ATP-binding-cassette transporter A1; however, there was no effect on the gene expression of either fatty acid synthase or sterol regulatory element binding protein-1. Reduction of ATP-binding-cassette transporter A1 mRNA levels was also observed in both liver and intestine of poloxamer 407-treated rats. When macrophages were cultured with poloxamer 407, the percent of cholesterol effluxed decreased in a concentration-dependent fashion, both in the absence and presence of a synthetic liver X receptor agonist. Lastly, total and unesterified (free) cholesterol concentrations were determined in the liver and 9 peripheral tissues of poloxamer 407- and saline-injected (control) rats. In every tissue, the concentration of total cholesterol for poloxamer 407-treated rats was significantly greater than the corresponding value for controls. Our findings would seem to suggest that the poloxamer 407-mediated reduction in both ATP-binding-cassette transporter A1 gene expression and cellular cholesterol efflux may potentially be one factor that contributes to the accumulation of cholesterol and cholesteryl esters in the liver and 9 peripheral tissues of poloxamer 407-treated rats. Furthermore, the surprising specificity by poloxamer 407 for inhibition of ATP-binding-cassette transporter A1 gene expression over fatty acid synthase and sterol regulatory element binding protein-1 may potentially be due to either disruption of a transcriptional cofactor required for ATP-binding-cassette transporter A1 gene expression, or enhanced turnover of ATP-binding-cassette transporter A1 mRNA.
Mesh Headings (Keywords): ATP-Binding Cassette Transporters, Animals, Cells, Cultured, Cholesterol, Dose-Response Relationship, Drug, Down-Regulation, Fatty Acid Synthetase Complex, Gene Expression, Humans, Intestines, Lipids, Liver, Macrophages, Male, Poloxamer, RNA, Messenger, Rats, Rats, Sprague-Dawley, Sterol Regulatory Element Binding Protein 1, Surface-Active Agents
Check for Full Text / PubMed Unique Identifier (PMID): 16603153
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