Inhibition of gastric H+, K(+)-ATPase by flavonoids: a structure-activity study.
Gastric H+, K(+)-ATPase plays a pivotal role in the final step of gastric acid secretion. Over 80 flavonoids, including flavones, flavanones, isoflavones and anthocyanidins were examined for their in vitro effect on gastric H+, K(+)-ATPase and some were found to be inhibitors of this enzyme. Kinetic studies showed that the inhibition of H+, K(+)-ATPase by flavonoids was competitive with respect to ATP, and non-competitive with respect to K+. Structure-activity analysis revealed the following: (1) The inhibitory potency of flavonoids depends on the number of hydroxyl groups up to four per molecule and that above this, no marked enhancement is seen; (2) The hydroxylation pattern is an important determinant of inhibitory potency. Two adjacent hydroxyl groups (catechol-type), three adjacent hydroxyl groups (pyrogallol-type) or hydroxyl groups at C-3, C-5 and C-7 are a minimum requirement for high potency inhibition; (3) Protection of the hydroxyl group(s) by glycosylation or methylation decreases potency; (4) Saturation of the C-2-C-3 double bond results in a decrease in potency; and (5) A ketone at C-4 is not essential for inhibition.
Murakami
S
S
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., Ohmiya, Japan. s12867@ccm.taisho.co.jp
Muramatsu
M
M
Tomisawa
K
K
D000818:Animals; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D006027:Glycosides / Q000494:pharmacology; D007529:Isoflavones / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D013270:Stomach / Q000201:enzymology*; D013329:Structure-Activity Relationship; D013552:Swine
D044950:Flavanones; D005419:Flavonoids; D006027:Glycosides; D007529:Isoflavones; D054328:Proton Pump Inhibitors; C028610:flavanone