TY - JOUR
T1 - Genistein, a competitive PDE1-4 inhibitor, may bind on high-affinity rolipram binding sites of brain cell membranes and then induce gastrointestinal adverse effects
AU - Shih, Chung Hung
AU - Lin, Ling Hong
AU - Lai, Ya Hsin
AU - Lai, Chi Yin
AU - Han, Cheng Ying
AU - Chen, Chien Ming
AU - Ko, Wun-Chang
N1 - Funding Information:
We would like to thank the CAPSi team and the health units of the city of Blumenau (Brazil) for their support
PY - 2010/9
Y1 - 2010/9
N2 - The affinities of genistein on phosphodiesterase (PDE)1-4 and cause of gastrointestinal adverse effects of genistein remain unclear. Female BALB/c mice were actively sensitized by intraperitoneal injections of ovalbumin and challenged by aerosolized ovalbumin (1%). After secondary challenge, aerosolized methacholine (6.25-50mg/ml) induced increases of enhanced pause (P enh) values in conscious mice in a concentration-dependent manner. Genistein (30-100μmol/kg, i.p.) markedly inhibited methacholine (12.5-50mg/ml)-induced increase of P enh value in the sensitized and challenged mice. In addition, genistein significantly reduced total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid, with the exception that lymphocytes and neutrophils were not significantly inhibited by genistein at the lowest dose (10μmol/kg). Genistein also markedly attenuated the release of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Genistein competitively inhibited PDE1-4, with a K i value ranging from 4.3 to 13.7μM. Genistein (3-300μM) concentration-dependently displaced 2nM [ 3H]-rolipram bound on high-affinity rolipram binding sites of brain cell membranes. The therapeutic ratio of genistein was calculated to be 7.9. Genistein (100μmol/kg, s.c.) significantly shortened xylazine/ketamine-induced anesthesia, suggesting that genistein administered at a higher dose may have gastrointestinal adverse effects. In conclusion, owing to the low therapeutic ratio of genistein, the gastrointestinal adverse effects may be induced via the binding of genistein on high-affinity rolipram binding sites of brain cell membranes, when it is used for a long term or at higher doses for treating allergies, asthma or chronic obstructive pulmonary disease.
AB - The affinities of genistein on phosphodiesterase (PDE)1-4 and cause of gastrointestinal adverse effects of genistein remain unclear. Female BALB/c mice were actively sensitized by intraperitoneal injections of ovalbumin and challenged by aerosolized ovalbumin (1%). After secondary challenge, aerosolized methacholine (6.25-50mg/ml) induced increases of enhanced pause (P enh) values in conscious mice in a concentration-dependent manner. Genistein (30-100μmol/kg, i.p.) markedly inhibited methacholine (12.5-50mg/ml)-induced increase of P enh value in the sensitized and challenged mice. In addition, genistein significantly reduced total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils in bronchoalveolar lavage fluid, with the exception that lymphocytes and neutrophils were not significantly inhibited by genistein at the lowest dose (10μmol/kg). Genistein also markedly attenuated the release of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Genistein competitively inhibited PDE1-4, with a K i value ranging from 4.3 to 13.7μM. Genistein (3-300μM) concentration-dependently displaced 2nM [ 3H]-rolipram bound on high-affinity rolipram binding sites of brain cell membranes. The therapeutic ratio of genistein was calculated to be 7.9. Genistein (100μmol/kg, s.c.) significantly shortened xylazine/ketamine-induced anesthesia, suggesting that genistein administered at a higher dose may have gastrointestinal adverse effects. In conclusion, owing to the low therapeutic ratio of genistein, the gastrointestinal adverse effects may be induced via the binding of genistein on high-affinity rolipram binding sites of brain cell membranes, when it is used for a long term or at higher doses for treating allergies, asthma or chronic obstructive pulmonary disease.
KW - Allergic asthma
KW - Cytokine
KW - Gastrointestinal adverse effect
KW - Genistein
KW - High-affinity rolipram binding site
KW - Phosphodiesterase isozymes 1-4 inhibition
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U2 - 10.1016/j.ejphar.2010.06.026
DO - 10.1016/j.ejphar.2010.06.026
M3 - Article
C2 - 20599919
AN - SCOPUS:77955085786
SN - 0014-2999
VL - 643
SP - 113
EP - 120
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1
ER -