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 aci d secretion. Over 80 flavonoids, including flavones, flavanones, isoflavone s 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 stu dies showed that the inhibition of H+, K+-ATPase by flavonoids was competit ive with respect to ATP, and non-competitive with respect to K+. Structure- activity analysis revealed the following: (1) The inhibitory potency of fla vonoids depends on the number of hydroxyl groups up to four per molecule an d that above this, no marked enhancement is seen; (2) The hydroxylation pat tern is an important determinant of inhibitory potency. Two adjacent hydrox yl 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 hydroxl group(s) by glycosylation or methylation decreases potency: (4) Saturation of the C-2-C-3 double bon d results in a decrease in potency; and (5) A ketone at C-4 is not essentia l for inhibition.