Helicobacter pylori urease belongs to a family of highly conserved urea-hydrolyzing enzymes. A common feature of these enzymes is the presence of two Lewis acid nickel ions and a reactive cysteine residue in the active site. The H+/K(+)-ATPase inhibitor omeprazole is a prodrug of a sulfenamide which covalently modifies cysteine residues on the luminal side of the H+/K(+)-ATPase of gastric parietal cells. Omeprazole and eight analogues were selected based on their chemical, electronic, and kinetic properties, and each was incubated with viable H. pylori in phosphate-buffered saline at pH 7.4 for 30 min, after which 100 mM urea was added and the amount of ammonia formed analyzed after a further 10 min. Inhibition between 0% and 100% at a 0.1 mM concentration was observed for the different analogues and could be expressed as a function of the pKa-value of the pyridine, the pKa-value of the benzimidazole, the overall lipophilicity, and, most importantly, the rate of sulfenamide formation, in a quantitative structure-activity relationship. The inhibition was potentiated by a lower pH (favoring the formation of the sulfenamide) but abolished in the presence of beta-mercaptoethanol (a scavenger of the sulfenamide). Structural analogues incapable of yielding the sulfenamide did not inhibit ammonia production. Treatment of Helicobacter felis-infected mice with 230 mumol/kg flurofamide b.i.d. for 4 weeks, known to potently inhibit urease activity in vivo, as a means of eradicating the infection, was tested and compared with the effect of 125 mumol/kg omeprazole b.i.d. for 4 weeks. Neither treatment proved efficacious.
Mammalian sodium/bile acid cotransporters (SBATs) constitute a subgroup of the sodium cotransporter superfamily and function in the enterohepatic circulation of bile acids. They are glycoproteins with an exoplasmic N-terminus, seven or nine transmembrane segments, and a cytoplasmic C-terminus. They exhibit no significant homology with other members of the sodium cotransporter family and there is limited structure/function information available for the SBATs. Membrane-impermeant methanethiosulfonates (MTS) inhibited bile acid transport by alkylation of cysteine 270 (apical SBAT)/266 (basolateral SBAT) that is fully conserved among the sodium/bile acid cotransporters. The accessibility of this residue to MTS reagent is regulated by the natural substrates, sodium and bile acid. In experiments with the apical SBAT, sodium alone increases the reactivity with the thiol reagents as compared to sodium-free medium. In contrast, bile acids protect the SBATs from inactivation, although only in the presence of sodium. The inhibition and protection data suggest that cysteine 270/266 lies in a sodium-sensitive region of the SBATs that is implicated in bile acid transport.
Female rats were treated orally for 3 mo with omeprazole (40 and 400 mumol/kg). Both doses caused total inhibition of gastric acid secretion and recovery was parallel to that of H+-K+-ATPase activity (30-50 and 60-80% inhibition 24 h after doses, respectively). The H+-K+-ATPase activity returned to control levels within 1 wk after the last dose. Plasma gastrin levels were dose-dependently increased during treatment but reversed to control levels within 9 days after the last dose. Parallel with a general increase in corpus mucosal mass, both pepsinogen and H+-K+-ATPase total content increased. However, their tissue concentrations did not differ from control values, suggesting that neither parietal nor chief cell density are changed by omeprazole treatment and also that their growth is parallel to the general hyperplasia. In contrast, the oxyntic mucosal histamine concentration was increased, indicating an increase in the enterochromaffin-like (ECL) cell density. Maximal capacity of the mucosa to secrete acid increased in parallel with the increase in mucosal mass and total H+-K+-ATPase content. However, basal acid secretion did not differ between treatment groups. Increased capacity slowly declined toward control levels over the 70-day recovery period after withdrawal of omeprazole. These results suggest that hypergastrinemia, induced in the rat by pharmacological inhibition of gastric acid secretion, causes a hyperplasia of oxyntic mucosal cells, ECL cells growing faster than the others. The hyperplastic mucosa has an increased capacity to produce acid and is functionally normal.
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