Genistein, a competitive PDE1-4 inhibitor, may bind on high-affinity rolipram binding sites of brain cell membranes and then induce gastrointestinal adverse effects

Chung Hung Shih, Ling Hong Lin, Ya Hsin Lai, Chi Yin Lai, Cheng Ying Han, Chien Ming Chen, Wun-Chang Ko

研究成果: 雜誌貢獻文章同行評審

7 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)113-120
頁數8
期刊European Journal of Pharmacology
643
發行號1
DOIs
出版狀態已發佈 - 九月 2010

ASJC Scopus subject areas

  • 藥理

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