Interferon-gamma increases expression of the di/tri-peptide transporter, h-PEPT1, and dipeptide transport in cultured human intestinal monolayers.
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 degrees 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) 28.6% compared to controls (p=0.03). In experiments conducted at 4 degrees C, Gly-Sar P(eff) decreased 39.6% in IFN-gamma treated cells (p=0.003) and 28.4% 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.
Foster
David R
DR
Department of Pharmacy Practice, Purdue University School of Pharmacy and Pharmaceutical Sciences, West Lafayette, IN, United States.
Landowski
Christopher P
CP
Zheng
Xiaomei
X
Amidon
Gordon L
GL
Welage
Lynda S
LS
D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D004151:Dipeptides / Q000378:metabolism; D017097:Electric Impedance; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D008353:Mannitol / Q000378:metabolism; D000074011:Peptide Transporter 1; D010539:Permeability; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters / Q000032:analysis / Q000502:physiology*
D004151:Dipeptides; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; C082186:SLC15A1 protein, human; D027981:Symporters; C004194:glycylsarcosine; D008353:Mannitol; D007371:Interferon-gamma