Abstract
Several amino acids, including L-glutamine (L-Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L-Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L-Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L-Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L-Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L-arginine, L-methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12.
| Original language | English |
|---|---|
| Pages (from-to) | 730-743 |
| Number of pages | 14 |
| Journal | Journal of Pharmaceutical Sciences |
| Volume | 91 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2002 |
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Keywords
- Absorption enhancer
- Amino acids
- Cytoprotection
- Heat shock protein 70
- Histamine
- Intracellular calcium
- Local toxicity
ASJC Scopus subject areas
- Drug Discovery
- Organic Chemistry
- Chemistry(all)
- Molecular Medicine
- Pharmacology
- Pharmaceutical Science
Cite this
Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium laurate, a drug absorption enhancer, in intestinal epithelium. / Endo, Yoko; Hanada, Kiyonori; Miyake, Masateru; Ogawara, Ken Ichi; Higaki, Kazutaka; Kimura, Toshikiro.
In: Journal of Pharmaceutical Sciences, Vol. 91, No. 3, 2002, p. 730-743.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mechanisms of cytoprotective effect of amino acids on local toxicity caused by sodium laurate, a drug absorption enhancer, in intestinal epithelium
AU - Endo, Yoko
AU - Hanada, Kiyonori
AU - Miyake, Masateru
AU - Ogawara, Ken Ichi
AU - Higaki, Kazutaka
AU - Kimura, Toshikiro
PY - 2002
Y1 - 2002
N2 - Several amino acids, including L-glutamine (L-Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L-Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L-Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L-Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L-Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L-arginine, L-methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12.
AB - Several amino acids, including L-glutamine (L-Gln), were found to protect the intestinal epithelial cells from the local toxicity caused by a drug absorption enhancer, sodium laurate (C12), in our previous study. To develop more efficient and safer formulations for enhancing drug absorption, the mechanisms of cytoprotection by amino acids were studied using rats and Caco-2 cells. Four amino acids, including L-Gln, could generally maintain the absorption-promoting action of C12, although taurine tended to attenuate it. Three amino acids, except for L-Gln, significantly suppressed the decrease in the transepithelial electrical resistance caused by C12. Quercetin, an inhibitor for biosynthesis of heat shock protein 70 (HSP70), masked only the protective effect of L-Gln in both rat large intestine and Caco-2 cells. Western blot analysis indicated clearly that HSP70 is induced extensively only by the addition of L-Gln in both rat large-intestinal cells and Caco-2 cells. C12 was found to increase the intracellular concentration of Ca2+ ([Ca2+]i) remarkably, and amino acids, especially L-arginine, L-methionine, and taurine, significantly attenuated the increase in [Ca2+]i caused by C12. Furthermore, although C12 stimulated the release of histamine, an inflammatory mediator, from rat large-intestinal tissue, amino acids were also found to suppress the release of histamine enhanced by C12. The results in the present study showed that an induction of HSP70, a decrease in [Ca2+]i elevated by C12, and a suppression of histamine release stimulated by C12 should be involved in the mechanisms behind the cytoprotective action of amino acids against the local toxicity caused by C12.
KW - Absorption enhancer
KW - Amino acids
KW - Cytoprotection
KW - Heat shock protein 70
KW - Histamine
KW - Intracellular calcium
KW - Local toxicity
UR - http://www.scopus.com/inward/record.url?scp=0036281181&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036281181&partnerID=8YFLogxK
U2 - 10.1002/jps.10049
DO - 10.1002/jps.10049
M3 - Article
C2 - 11920758
AN - SCOPUS:0036281181
VL - 91
SP - 730
EP - 743
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
SN - 0022-3549
IS - 3
ER -