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Multiple inhibitory effects of genistein on stimulus-secretion coupling in rat pancreatic acini.

Duan, Rui-Dong LU ; Andreas, C; Wagner, C; Yule, David and Williams, John A (1994) In American Journal of Physiology 266(2). p.303-310
Abstract
Genistein, a tyrosine kinase inhibitor, inhibited cholecystokinin (CCK)-induced maximal amylase release from rat pancreatic acini by 18, 31, and 46% at concentrations of 100, 300, and 750 microM, respectively, after 30 min preincubation. Genistein similarly decreased amylase release stimulated by bombesin but not that stimulated by secretin or vasoactive intestinal peptide. The steps of stimulus-secretion coupling affected by genistein were further evaluated. We found genistein dose dependently suppressed CCK-as well as NaF-induced polyphosphoinositide hydrolysis with a 50% inhibitory concentration of 380 and 400 microM, respectively, but only slightly suppressed the increase of intracellular Ca2+ concentration in response to either low or... (More)
Genistein, a tyrosine kinase inhibitor, inhibited cholecystokinin (CCK)-induced maximal amylase release from rat pancreatic acini by 18, 31, and 46% at concentrations of 100, 300, and 750 microM, respectively, after 30 min preincubation. Genistein similarly decreased amylase release stimulated by bombesin but not that stimulated by secretin or vasoactive intestinal peptide. The steps of stimulus-secretion coupling affected by genistein were further evaluated. We found genistein dose dependently suppressed CCK-as well as NaF-induced polyphosphoinositide hydrolysis with a 50% inhibitory concentration of 380 and 400 microM, respectively, but only slightly suppressed the increase of intracellular Ca2+ concentration in response to either low or high concentrations of CCK. Genistein at 300 microM also decreased incorporation of [3H]inositol into phosphatidylinositol 4,5-bisphosphate. Most strikingly, 300 microM genistein inhibited Ca(2+)-stimulated amylase release by 85% in streptolysin O-permeabilized acini and thapsigargin-stimulated amylase release by 69% in intact acini. Daidzein, the inactive analogue of genistein, had no effect on any of the above parameters. Genistein, up to 750 microM, did not affect amylase release in response to phorbol ester. To relate these inhibitory effects of genistein to its inhibition of tyrosine phosphorylation, Western blotting was performed with an anti-phosphotyrosine monoclonal antibody. Genistein at 100 microM partly and at 300 microM completely inhibited CCK-induced tyrosine phosphorylation. In conclusion, genistein inhibits amylase release at multiple stages of stimulus-secretion coupling. These effects most likely involve both tyrosine kinase-dependent and -independent mechanisms. (Less)
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Contribution to journal
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American Journal of Physiology
volume
266
issue
2
pages
8 pages
publisher
American Physiological Society
external identifiers
  • scopus:0027995830
ISSN
0002-9513
DOI
10.1152/ajpgi.1994.266.2.G303
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English
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bc36b181-2f32-4cd2-8a53-ad5224b9e9e5
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@article{bc36b181-2f32-4cd2-8a53-ad5224b9e9e5,
  abstract     = {Genistein, a tyrosine kinase inhibitor, inhibited cholecystokinin (CCK)-induced maximal amylase release from rat pancreatic acini by 18, 31, and 46% at concentrations of 100, 300, and 750 microM, respectively, after 30 min preincubation. Genistein similarly decreased amylase release stimulated by bombesin but not that stimulated by secretin or vasoactive intestinal peptide. The steps of stimulus-secretion coupling affected by genistein were further evaluated. We found genistein dose dependently suppressed CCK-as well as NaF-induced polyphosphoinositide hydrolysis with a 50% inhibitory concentration of 380 and 400 microM, respectively, but only slightly suppressed the increase of intracellular Ca2+ concentration in response to either low or high concentrations of CCK. Genistein at 300 microM also decreased incorporation of [3H]inositol into phosphatidylinositol 4,5-bisphosphate. Most strikingly, 300 microM genistein inhibited Ca(2+)-stimulated amylase release by 85% in streptolysin O-permeabilized acini and thapsigargin-stimulated amylase release by 69% in intact acini. Daidzein, the inactive analogue of genistein, had no effect on any of the above parameters. Genistein, up to 750 microM, did not affect amylase release in response to phorbol ester. To relate these inhibitory effects of genistein to its inhibition of tyrosine phosphorylation, Western blotting was performed with an anti-phosphotyrosine monoclonal antibody. Genistein at 100 microM partly and at 300 microM completely inhibited CCK-induced tyrosine phosphorylation. In conclusion, genistein inhibits amylase release at multiple stages of stimulus-secretion coupling. These effects most likely involve both tyrosine kinase-dependent and -independent mechanisms.},
  author       = {Duan, Rui-Dong and Andreas, C and Wagner, C and Yule, David and Williams, John A},
  issn         = {0002-9513},
  language     = {eng},
  number       = {2},
  pages        = {303--310},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology},
  title        = {Multiple inhibitory effects of genistein on stimulus-secretion coupling in rat pancreatic acini.},
  url          = {http://dx.doi.org/10.1152/ajpgi.1994.266.2.G303},
  volume       = {266},
  year         = {1994},
}