Restoration of acid secretion following treatment with proton pump inhibitors.
OBJECTIVE
Proton pump inhibitors (PPIs) are covalent inhibitors of the gastric H+,K+-adenosine triphosphatase (ATPase) forming disulfide bonds. Recovery of acid secretion after PPI inhibition may be due to de novo synthesis of pump protein and/or disulfide reduction and reactivation of inhibited pump. The half-time of recovery of acid secretion in rats following omeprazole treatment is approximately 15 hours, whereas pump protein half-life is 54 hours. In humans, the half-life of the inhibitory effect on acid secretion is approximately 28 hours for omeprazole and approximately 46 hours for pantoprazole. Whereas all PPIs bind to cysteine 813, pantoprazole additionally binds to cysteine 822, deeper in the membrane domain of TM6. Their different durations of action may reflect different rates of pump reactivation due to differing accessibility of the disulfides to glutathione.


METHODS
Rats were stimulated and treated with 30 mg/kg of each PPI. Gastric ATPase was prepared and reversal of inhibition of the H+,K+-ATPase was measured as the time-dependent restoration of activity by incubation with dithiothreitol or glutathione.


RESULTS
One hundred percent reactivation of ATPase following inhibition in vivo by omeprazole or its enantiomers was seen with dithiothreitol and 89% with glutathione. Similar data were found for lansoprazole or rabeprazole. No reactivation by either reducing agent was seen following inhibition by pantoprazole.


CONCLUSIONS
Recovery of acid secretion following inhibition by all PPIs, other than pantoprazole, may depend on both protein turnover and reversal of the inhibitory disulfide bond. In contrast, recovery of acid secretion after pantoprazole may depend entirely on new protein synthesis.
Shin
Jai Moo
JM
Department of Physiology and Medicine, University of California at Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.
Sachs
George
G
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005978:Glutathione / Q000494:pharmacology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D066298:In Vitro Techniques; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology; D054328:Proton Pump Inhibitors; D064750:Rabeprazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000201:enzymology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; D064750:Rabeprazole; D017506:H(+)-K(+)-Exchanging ATPase; D005978:Glutathione; D009853:Omeprazole; D004229:Dithiothreitol