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J. Biol. Chem., Vol. 260, Issue 8, 4591-4597, 04, 1985

Omeprazole, a specific inhibitor of gastric (H+-K+)-ATPase, is a H+- activated oxidizing agent of sulfhydryl groups

WB Im, JC Sih, DP Blakeman and JP McGrath

Omeprazole (5-methoxy-2-[[(4-methoxy-3,5- dimethylpyridinyl)methyl]sulfinyl]-1H-benzimidazole) appeared to inhibit gastric (H+-K+)-ATPase by oxidizing its essential sulfhydryl groups, since the gastric ATPase inactivated by the drug in vivo or in vitro recovered its K+-dependent ATP hydrolyzing activity upon incubation with mercaptoethanol. Biological reducing agents like cysteine or glutathione, however, were unable to reverse the inhibitory effect of omeprazole. Moreover, acidic environments enhanced the potency of omeprazole. For example, in vivo pretreatment of rats with carbachol, a secretagogue, enhanced the activity of omeprazole to inhibit gastric (H+-K+)-ATPase, while pretreatment with cimetidine, an antisecretory agent, reduced its potency. In vitro, lowering pH of incubation media from 7.4 to 5.0 improved the ability of omeprazole to inhibit hog gastric (H+-K+)-ATPase almost 60-fold. The inhibitory effect of the drug was accompanied by a dose-dependently decreased amount of free sulfhydryl groups in the isolated hog gastric membranes. The chemical reactivity of omeprazole with mercaptans is also consistent with the biological action of omeprazole. The drug, only under acidic conditions, reacted with a stoichiometric amount of ethyl mercaptan (or beta-mercaptoethanol) to produce regio-isomers of N- sulfenylated omeprazole sulfide (5-methoxy-2[[(4-methoxy-3,5- dimethyl- 2-pyridinyl)methyl]thio]-1- or 3-(ethylthio)benzimidazole). The N- sulfenylated compound reacted at neutral pH with another stoichiometric amount of ethyl mercaptan to produce omeprazole sulfide quantitatively. The gastric polypeptides of 100 kilodaltons representing (H+-K+)-ATPase in the rat gastric mucosa or isolated hog gastric membranes were covalently labeled with [14C]omeprazole. The radioactive label bound to the ATPase, however, could not be displaced by mercaptoethanol under the identical conditions where the ATPase activity was fully restored. These observations suggest that the essential sulfhydryl groups which reacted with omeprazole did not form a stable covalent bond with the drug, but rather that they further reacted with adjacent sulfhydryl groups to form disulfides which could be reduced by mercaptoethanol.
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