Cisplatin upregulates glutamine transport in human intestinal epithelial cells: the protective mechanism of glutamine on intestinal mucosa after chemotherapy.
BACKGROUND
Glutamine (GLN) prevents the intestinal mucosal injury induced by chemotherapy, although the mechanism of this protective action has not yet been elucidated. Amino acid transport across the plasma membrane is essential for supplying enterocytes with amino acids for cellular metabolism. It was hypothesized that chemotherapy stimulates GLN transport, which enables GLN to be used more efficiently as a metabolic fuel.


METHODS
A rat model was used to examine the effect of enteral GLN on intestinal mucosal injury induced by intraperitoneal injection of cisplatin (7.0 mg/kg of body weight). The effects of cisplatin on amino acid transport and the expression of messenger RNA and protein were evaluated by real-time polymerase chain reaction and Western blot analysis, respectively, in the human intestinal epithelial cell line Caco-2. The effects of cisplatin on glutaminase activity and intracellular glutathione were also studied.


RESULTS
GLN prevented mucosal atrophy induced by cisplatin in rats. In Caco-2 cells, cisplatin significantly increased GLN transport and the expression of GLN transporter ASCT2 messenger RNA and protein. Leucine, but not glutamate, transport significantly increased in the cisplatin-treated group due to the increase in LAT1 (leucine transporter) protein expression. Glutaminase activity and intracellular glutathione increased significantly in the cisplatin-treated group.


CONCLUSIONS
Bolus enteral GLN prevents intestinal mucosal injury induced by cisplatin in rats, as demonstrated by increased GLN transport and increased GLN transporter expression after cisplatin administration.
Nose
Satoko
S
Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. noses@pedsurg.med.osaka-u.ac.jp
Wasa
Masafumi
M
Tazuke
Yuko
Y
Owari
Mitsugu
M
Fukuzawa
Masahiro
M
D026962:Amino Acid Transport System ASC / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D004750:Enteral Nutrition; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005765:Gastrointestinal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007930:Leucine / Q000378:metabolism; D008297:Male; D015778:Minor Histocompatibility Antigens; D023421:Models, Animal; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D026962:Amino Acid Transport System ASC; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D005973:Glutamine; D005972:Glutaminase; D005978:Glutathione; D007930:Leucine; D002945:Cisplatin