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.