Enhanced glucose absorption in the rat small intestine following repeated doses of 5-fluorouracil.
Many studies demonstrated that 5-fluorouracil (5-FU) treatment of rodents caused the damage of small intestine, resulting in the malabsorption, while we recently found that repeated administration of 5-FU to rats increased Na(+)-dependent glucose absorption in the small intestine. This study investigated the cause of enhanced glucose absorption. 3-O-methyl-d-glucose (3-OMG) absorption was examined using the everted intestine technique. d-Glucose uptake, phlorizin binding, Western blot analysis and membrane fluidity were examined using small intestinal brush-border membrane vesicles (BBMV). Repeated oral administration of 5-FU to rats increased Na(+)-dependent 3-OMG absorption in the small intestine, while alkaline phosphatase activity in the small intestine decreased. Na(+)/K(+)-ATPase activity of 5-FU-treated rats was about three-fold higher than that of control rats. Although the amount of Na(+)-dependent glucose co-transporter (SGLT1) in 5-FU-treated rats decreased, the overshoot magnitude of d-glucose uptake in BBMV was not altered. Maximum binding of phlorizin in 5-FU-treated rats was 1.5-fold larger than that of control rats, but not altered the maximal rate of d-glucose absorption, Michaelis constant of d-glucose and dissociation constant of phlorizin. The membrane fluidity of 5-FU-treated rats increased. The enhanced d-glucose absorption in 5-FU-treated rats seems to occur secondarily due to the activation of Na(+)/K(+)-ATPase activity in basolateral membranes (BLM). Because the amounts of SGLT1 in 5-FU-treated rats decreased, the increase of turnover rate of SGLT1 and/or an expression of unknown Na(+)-dependent glucose co-transporter with high affinity for d-glucose and phlorizin sensitivity would contribute to the enhancement of d-glucose transport in 5-FU-treated rats.
Tomimatsu
Takashi
T
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
Horie
Toshiharu
T
D019325:3-O-Methylglucose / Q000378:metabolism; D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity*; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007408:Intestinal Absorption / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism; D008727:Methotrexate / Q000633:toxicity; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010695:Phlorhizin / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D019325:3-O-Methylglucose; D010695:Phlorhizin; D000469:Alkaline Phosphatase; D000254:Sodium-Potassium-Exchanging ATPase; D005947:Glucose; D005472:Fluorouracil; D008727:Methotrexate