Inhibition of Gastric H⁺,K⁺-ATPase by Flavonoids: A Structure-Activity Study

Abstract

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 hydroxl 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.

Key Words:

• Flavonoids
• H⁺, K⁺-ATPase
• Proton pump
• Enzyme inhibitor