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Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships.
Biochem Pharmacol. 2004 Nov 15; 68(10):2087-94.BP

Abstract

The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart. The IC(50) values of PDE1-5 were greater than those reported previously for the reference drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-, 5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20 microM, as did genistein except with a low potency on PDE5. Daidzein, an inactive analogue of genistein in tyrosine kinase inhibition, showed selective inhibition of PDE3 with an IC(50) value of around 30 microM, as did eriodictyol with an IC(50) value of around 50 microM. Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM, respectively. Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4 with an IC(50) value of around 40 microM. Diosmetin more-selectively inhibited PDE2 (IC(50) of 4.8 microM) than PDE1, PDE4, or PDE5. However, biochanin A more-selectively inhibited PDE4 (IC(50) of 8.5 microM) than PDE1 or PDE2. Apigenin inhibited PDE1-3 with IC(50) values of around 10-25 microM. Myricetin inhibited PDE1-4 with IC(50) values of around 10-40 microM. The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC(50) of < 10 microM). In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study.

Authors+Show Affiliations

Ko WC
Graduate Institute of Pharmacology, College of Medicine, Taipei Medical University, Taipei, Taiwan. wc_ko@tmu.edu.tw
Shih CM
No affiliation info available
Lai YH
No affiliation info available
Chen JH
No affiliation info available
Huang HL
No affiliation info available

MeSH

3',5'-Cyclic-AMP Phosphodiesterases3',5'-Cyclic-GMP PhosphodiesterasesAnimalsCyclic Nucleotide Phosphodiesterases, Type 1Cyclic Nucleotide Phosphodiesterases, Type 2Cyclic Nucleotide Phosphodiesterases, Type 3Cyclic Nucleotide Phosphodiesterases, Type 4Cyclic Nucleotide Phosphodiesterases, Type 5FlavonoidsGuinea PigsIsoenzymesPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesQuercetinStructure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15476679

Citation

Ko, Wun-Chang, et al. "Inhibitory Effects of Flavonoids On Phosphodiesterase Isozymes From Guinea Pig and Their Structure-activity Relationships." Biochemical Pharmacology, vol. 68, no. 10, 2004, pp. 2087-94.
Ko WC, Shih CM, Lai YH, et al. Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochem Pharmacol. 2004;68(10):2087-94.
Ko, W. C., Shih, C. M., Lai, Y. H., Chen, J. H., & Huang, H. L. (2004). Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. Biochemical Pharmacology, 68(10), 2087-94.
Ko WC, et al. Inhibitory Effects of Flavonoids On Phosphodiesterase Isozymes From Guinea Pig and Their Structure-activity Relationships. Biochem Pharmacol. 2004 Nov 15;68(10):2087-94. PubMed PMID: 15476679.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships. AU - Ko,Wun-Chang, AU - Shih,Chwen-Ming, AU - Lai,Ya-Hsin, AU - Chen,Jun-Hao, AU - Huang,Hui-Lin, PY - 2004/03/26/received PY - 2004/06/29/accepted PY - 2004/10/13/pubmed PY - 2005/1/26/medline PY - 2004/10/13/entrez SP - 2087 EP - 94 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 68 IS - 10 N2 - The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart. The IC(50) values of PDE1-5 were greater than those reported previously for the reference drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-, 5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20 microM, as did genistein except with a low potency on PDE5. Daidzein, an inactive analogue of genistein in tyrosine kinase inhibition, showed selective inhibition of PDE3 with an IC(50) value of around 30 microM, as did eriodictyol with an IC(50) value of around 50 microM. Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM, respectively. Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4 with an IC(50) value of around 40 microM. Diosmetin more-selectively inhibited PDE2 (IC(50) of 4.8 microM) than PDE1, PDE4, or PDE5. However, biochanin A more-selectively inhibited PDE4 (IC(50) of 8.5 microM) than PDE1 or PDE2. Apigenin inhibited PDE1-3 with IC(50) values of around 10-25 microM. Myricetin inhibited PDE1-4 with IC(50) values of around 10-40 microM. The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC(50) of < 10 microM). In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study. SN - 0006-2952 UR - https://www.unboundmedicine.com/medline/citation/15476679/Inhibitory_effects_of_flavonoids_on_phosphodiesterase_isozymes_from_guinea_pig_and_their_structure_activity_relationships_ DB - PRIME DP - Unbound Medicine ER -