Sulfide and sulfoxide derivatives of substituted benzimidazoles inhibit acid formation in isolated gastric glands by different mechanisms.
The sulfoxide and sulfide forms of three pairs of substituted benzimidazoles, including omeprazole, were investigated using isolated gastric glands and microsomal membranes containing H+,K+-adenosine Triphosphatase (ATPase). The sulfoxides inhibited stimulated aminopyrine (AP) uptake giving IC50 values between 0.47 and 1.1 microM, whereas the sulfides were less potent and showed a greater variation in IC50 values, 9.5 to 170 microM. The decrease in stimulated oxygen consumption induced by the sulfoxides was parallel to their inhibition of AP-uptake, with IC50 values of 0.40 to 3.7 microM, whereas the sulfides were virtually without effect, IC50 greater than 100 microM. The permeable buffers imidazole and 2,6-dimethylpyridine mimiced the effect of the sulfides on both AP accumulation and oxygen consumption. When tested on H+, K+-ATPase, an enzyme suggested to be the proton pump of the gastric mucosa, the sulfoxides inhibited the ATPase activity with IC50 values between 0.25 to 2.8 microM, in contrast to the sulfides, which were without inhibitory action. The sulfoxide-induced inhibition of AP-uptake in gastric glands and H+, K+-ATPase activity was prevented by the addition of beta-mercaptoethanol, whereas the mercaptane was without effect on sulfide-induced inhibition of AP-accumulation. When tested on vesicles containing H+, K+-ATPase, both the sulfide and sulfoxide derivatives dissipated the proton gradient generated by the enzyme, but only the sulfoxide-induced inhibition was prevented by the addition of beta-mercaptoethanol.(ABSTRACT TRUNCATED AT 250 WORDS)
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase; D066298:In Vitro Techniques; D008297:Male; D008623:Mercaptoethanol / Q000494:pharmacology; D009853:Omeprazole / Q000031:analogs & derivatives; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D013440:Sulfides / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology
D001562:Benzimidazoles; D013440:Sulfides; D013454:Sulfoxides; D000632:Aminopyrine; D008623:Mercaptoethanol; C040449:omeprazole sulfide; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole