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 [3H]-rolipram binding and reversing xylazine/ketamine-induced anesthesia. The reversing effect was reported to occur through a presynaptic α2-adrenoceptor inhibition and trigger vomiting in ferrets. In contrast, clonidine, an α2-adrenoceptor agonist, prevented emesis induced by PDE4 inhibitors in ferrets. According to the Lineweaver-Burk analysis, luteolin (3-30 μM) competitively inhibited PDE1-5 activities, with Ki values of 15.0, 6.4, 13.9, 11.1, and 9.5 μM, respectively, which did not significantly differ from each other. The equilibrium dissociation constant (Kd) and maximal density (Bmax) for [3H]-rolipram binding at high-affinity rolipram binding sites of guinea pig brain cell membranes were 10.1 nM and 3.7 pmol/g of tissue, respectively. The EC50 (PDE4H) values of luteolin and Ro 20-1724, a selective PDE4 inhibitor, for displacing 2 nM [3H]-rolipram binding were 11.2 μM and 45.6 nM, respectively. The therapeutic (PDE4H/PDE4L) ratios of luteolin and Ro 20-1724 were calculated to be 0.6, and 0.004, respectively. Both luteolin (10-30 μmol/kg, s.c.) and Ro 20-1724 (0.1-1 μmol/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 (PDE4H/PDE4L) 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.
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