Enhanced absorption of 3-O-methyl glucose following gastrointestinal injury induced by repeated oral administration of 5-FU in mice.
The absorption of nutrients is mainly mediated by specific carriers and generally retarded following gastrointestinal injury. The aim of this study was to assess the effect of repeated oral administration of 5-fluorouracil (5-FU) on the intestinal absorption of glucose by using 3-O-methyl-D-glucose (3-OMG), a glucose analogue that is not metabolized, as a probe. Repeated administration of 5-FU (60 mg/kg/day for 3 days) readily induced intestinal mucosal injury assessed by visual observation and loss of intestinal wet weight. At the same time, the carrier-dependent absorption clearance of 3-OMG was increased 1.8-fold, while the carrier-independent absorption assessed by L-glucose transport was not affected. Phloretin, a glucose transporter 2 (GLUT2) inhibitor, completely abolished the absorption of 3-OMG in both control and 5-FU-treated mice, indicating the specific effect on the carrier-dependent process. Protein and mRNA expressions of GLUT2 were significantly higher in 5-FU-treated mice compared to the control mice. Sodium (Na(+)) glucose co-transporter 1 (SGLT1) expressions were also moderately elevated in 5-FU-treated mice. Concomitantly, the uptake of D-glucose into both isolated brush border and basolateral membrane vesicles was significantly increased. These results indicate that repeated oral administration of 5-FU did not hamper, but unexpectedly induced, SGLT1 and GLUT2 expression to enhance glucose absorption.
Laboratory of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, Chiba 260-8675, Japan.
Tomoko
T
Hakata
Kousei
K
Ito
Toshiharu
T
Horie
D019325:3-O-Methylglucose / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D005472:Fluorouracil; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D051273:Glucose Transporter Type 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D010693:Phloretin / Q000494:pharmacology; D051269:Sodium-Glucose Transporter 1 / Q000096:biosynthesis; D013997:Time Factors
D051273:Glucose Transporter Type 2; C495675:Slc5a1 protein, mouse; D051269:Sodium-Glucose Transporter 1; D019325:3-O-Methylglucose; D005947:Glucose; D010693:Phloretin; D005472:Fluorouracil