Inhibition of metallopeptidases by flavonoids and related compounds.
To elucidate possible mechanisms of activity in medicinal plants containing flavonoids, the inhibitory potency of twenty flavones, flavonols, flavanones, phenylacrylic acids and various hydroxylated phenylacetic acids on the activity of neutral endopeptidase (NEP; EC 3.4.24.11), angiotensin-converting enzyme (ACE; EC 3.4.15.1) and aminopeptidase N (APN; EC 3.4.11.2) was investigated in vitro. The screening generally resulted that inhibition of these enzymes requires free hydroxyl groups at the flavone molecule. Flavone and methoxylated compounds (sinensetin) were without effects. Flavonoids with free hydroxyl functions in position 3',4' and 5,7 inhibited the activity of NEP (quercetin, luteolin, fisetin), with myricetin (IC50 = 42 microM) as strongest inhibitor. Inhibition of ACE and APN did not depend on this class of compounds and substitution pattern. E.g. 3,4-dihydroxyphenylacetic acid and 4-methylcatechol (urinary metabolites of flavonoids) also inhibited both APN and ACE activity, but not NEP activity. The results demonstrate that some of the pharmacological activities of flavonoids might be related to the inhibition of metallopeptidases responsible for the splitting of regulatory neuropeptides.
Bormann
H
H
Humboldt-Universität zu Berlin, Institut für Pharmazie, Germany.
Melzig
M F
MF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000201:enzymology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*; D013094:Spermatozoa / Q000201:enzymology; D013329:Structure-Activity Relationship; D013552:Swine
D000806:Angiotensin-Converting Enzyme Inhibitors; D005419:Flavonoids; D011480:Protease Inhibitors; D018826:CD13 Antigens; D008666:Metalloendopeptidases; D015260:Neprilysin