Department of Internal Medicine, Taipei Municipal Wan-Fang Hospital, Taiwan.
Eur J Pharmacol. 2010 Feb 10;627(1-3):269-75. doi: 10.1016/j.ejphar.2009.10.031. Epub 2009 Oct 22.
The aim of the present study was to investigate the mode of action of luteolin on phisphodiesterase (PDE) 1-5, and the possible adverse effects, such as nausea, vomiting, and gastric hypersecretion, determined by replacing [(3)H]-rolipram binding and reversing xylazine/ketamine-induced anesthesia. The reversing effect was reported to occur through a presynaptic alpha(2)-adrenoceptor inhibition and trigger vomiting in ferrets. In contrast, clonidine, an alpha(2)-adrenoceptor agonist, prevented emesis induced by PDE4 inhibitors in ferrets. According to the Lineweaver-Burk analysis, luteolin (3-30 microM) competitively inhibited PDE1-5 activities, with K(i) values of 15.0, 6.4, 13.9, 11.1, and 9.5 microM, respectively, which did not significantly differ from each other. The equilibrium dissociation constant (K(d)) and maximal density (B(max)) for [(3)H]-rolipram binding at high-affinity rolipram binding sites of guinea pig brain cell membranes were 10.1 nM and 3.7 p mol/g of tissue, respectively. The EC(50) (PDE4(H)) values of luteolin and Ro 20-1724, a selective PDE4 inhibitor, for displacing 2 nM [(3)H]-rolipram binding were 11.2 microM and 45.6 nM, respectively. The therapeutic (PDE4(H)/PDE4(L)) ratios of luteolin and Ro 20-1724 were calculated to be 0.6, and 0.004, respectively. Both luteolin (10-30 micromol/kg, s.c.) and Ro 20-1724 (0.1-1 micromol/kg, s.c.) significantly reversed the xylazine/ketamine-induced anesthesia in mice. Although luteolin non-selectively and competitively inhibited PDE1-5, only PDE4 inhibition contributed to a reversing effect. In conclusion, because of the low therapeutic (PDE4(H)/PDE4(L)) ratio of luteolin, the gastrointestinal adverse effects such as nausea, vomiting and gastric hypersecretion should be carefully monitored, whenever luteolin is used for treating allergies, asthma or chronic obstructive pulmonary disease.
本研究旨在探讨木樨草素对磷酸二酯酶（PDE）1-5 的作用模式，以及可能的不良反应，如恶心、呕吐和胃酸分泌过多，通过取代 [(3)H]-rolipram 结合和逆转氯胺酮/酮诱导的麻醉来确定。据报道，这种逆转作用是通过突触前 α2-肾上腺素能受体抑制和引发雪貂呕吐来实现的。相比之下，可乐定，一种 α2-肾上腺素能受体激动剂，可防止 PDE4 抑制剂在雪貂中引起呕吐。根据 Lineweaver-Burk 分析，木樨草素（3-30 μM）竞争性抑制 PDE1-5 活性，其 K(i) 值分别为 15.0、6.4、13.9、11.1 和 9.5 μM，彼此之间无显著差异。高亲和力 rolipram 结合位点的豚鼠脑细胞质膜 [(3)H]-rolipram 结合的平衡解离常数（K(d)）和最大密度（B(max)）分别为 10.1 nM 和 3.7 pmol/g 组织。木樨草素和罗匹隆-1724（一种选择性 PDE4 抑制剂）对置换 2 nM [(3)H]-rolipram 结合的 EC50（PDE4（H））值分别为 11.2 μM 和 45.6 nM。木樨草素和罗匹隆-1724 的治疗（PDE4（H）/PDE4（L））比值分别计算为 0.6 和 0.004。木樨草素（10-30 μmol/kg，皮下注射）和罗匹隆-1724（0.1-1 μmol/kg，皮下注射）均能显著逆转氯胺酮/酮诱导的小鼠麻醉。虽然木樨草素非选择性和竞争性抑制 PDE1-5，但只有 PDE4 抑制有助于逆转作用。总之，由于木樨草素的治疗（PDE4（H）/PDE4（L））比值较低，因此在治疗过敏、哮喘或慢性阻塞性肺疾病时，应密切监测恶心、呕吐和胃酸分泌过多等胃肠道不良反应。
