Journal
PHARMACOLOGICAL RESEARCH
Volume 59, Issue 3, Pages 215-220Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2008.11.001
Keywords
h-PEPT1; Interferon-gamma; Caco-2 cells
Categories
Funding
- University of Michigan College of Pharmacy
- NIH/NIGMS [5 R01 GM37188]
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The di/tri-peptide transporter h-PEPT1 plays an important role in the oral absorption of di/tri-peptides and numerous drugs. Inflammatory conditions may influence intestinal xenobiotic transporter function: however, the effects of inflammation on h-PEPT1 have not been well described. This study was conducted to determine the effects of the inflammatory cytokine interferon-gamma (IFN-gamma) on h-PEPT1 mediated dipeptide absorption. Caco-2 monolayers were grown on permeable supports. The effective apical-to-basolateral permeability (P-eff) of glycylsarcosine (Gly-Sar) was measured following incubation with IFN- gamma or control media. Additional experiments were conducted at 4 C, and with escalating concentrations of Gly-Sar. h-PEPT1 expression was determined using semiquantitative RT-PCR. IFN-gamma 50 ng/ml increased Gly-Sar P-eff 28.61, compared to controls (p=0.03). in experiments conducted at 4 C, Gly-Sar P-eff decreased 39.6% in IFN-gamma treated cells (p=0.003) and HAT. in controls (p=0.006). In controls and IFN-gamma treated cells, concentration dependent transport was seen with escalating concentrations of Gly-Sar. Compared to controls, IFN-gamma 50 and 100 ng/ml increased h-PEPT1 mRNA expression by 14.2% and 11.5%, respectively (p = 0.019). In summary, IFN-gamma increases h-PEPT1 expression and permeation of the dipeptide Gly-Sar in Caco-2 monolayers. These findings imply that intestinal absorption of peptides and peptidomimetic drugs may be increased in certain inflammatory conditions. (C) 2008 Elsevier Ltd. All rights reserved.
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