Misako Takashima

CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans

Omeprazole is metabolized by genetically determined S‐mephenytoin 4′‐hydroxylase (CYP2C19) in the liver. This study aimed to determine whether the effect of omeprazole on intragastric pH depends on CYP2C19 genotype status.

Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin

Proton pump inhibitors such as omeprazole and lansoprazole are mainly metabolized by CYP2C19 in the liver. The therapeutic effects of proton pump inhibitors are assumed to depend on CYP2C19 genotype status.

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH

Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non‐enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual’s CYP2C19 status.

Effects of Helicobacter pylori infection on gastric acid secretion and serum gastrin levels in Mongolian gerbils

BACKGROUND AND AIMS Body gastritis caused by Helicobacter pylori infection appears to inhibit gastric acid secretion. The aim of this study was to determine the effects ofH pylori infection on gastric acid secretion and clarify its mechanisms with reference to interleukin 1β (IL-1β). METHODS (1) Mongolian gerbils were inoculated orally with H pylori. Before, six, and 12 weeks after inoculation, serum gastrin levels, gastric acid output, and IL-1β mRNA levels in the gastric mucosa were determined. Pathological changes were also determined according to the updated Sydney system. (2) Effects of recombinant human IL-1 receptor antagonist (rhIL-1ra) on gastric acid output and serum gastrin levels were also determined. RESULTS (1) Scores for activity and inflammation of gastritis and serum gastrin levels were significantly increased, and gastric acid output was significantly decreased six and 12 weeks after inoculation withH pylori. IL-1β mRNA levels in the gastric mucosa were also elevated six and 12 weeks after inoculation withH pylori. (2) Acid output and serum gastrin levels in the infected groups returned to control levels after rhIL-1ra injection. CONCLUSIONS Gastric acid secretion is decreased and serum gastrin levels are increased in Mongolian gerbils infected with H pylori. This change in gastric acid secretion appears to be mediated by IL-1β induced by H pylori infection.

Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin.

Rabeprazole is a potent proton pump inhibitor and is mainly reduced to thioether rabeprazole by a non-enzymatic pathway and partially metabolized to demethylated rabeprazole by CYP2C19 in the liver. We intended to determine a cure rate for Helicobacter pylori infection by dual rabeprazole/amoxicillin therapy in relation to CYP2C19 genotype status prospectively. Ninety-seven patients with gastritis and H. pylori infection completed the dual therapy with 10 mg of rabeprazole bid and 500 mg of amoxicillin tid for 2 weeks. At 1 month after treatment, cure of H. pylori infection was assessed on the basis of histology, a rapid urease test, culture, polymerase chain reaction (PCR), and 13C-urea breath test. CYP2C19 genotype status was determined by a PCR-restriction fragment length polymorphism method. Of the 97 patients, 33 were homozygous extensive metabolizers (homEM), 48 were heterozygous extensive metabolizers (hetEM), and 16 were poor metabolizers (PM). Cure of H. pylori infection was achieved in 79 of the 97 patients (81.4%, 95%CI = 71.9-88.7). Significant differences in cure rates among the homEM, hetEM, and PM groups were observed; 60.6% (95%CI = 42.1-77.3), 91.7% (95%CI = 80.0-97.7), and 93.8% (95%CI = 69.8-99.8), respectively (P = 0.0007). Twelve patients without cure after initial treatment (10 homEMs and 2 hetEMs) were successfully retreated with rabeprazole 10 mg q.i.d. and amoxicillin 500 mg q.i.d. for 2 weeks. The cure rates for H. pylori infection by dual rabeprazole/amoxicillin therapy depended on the CYP2C19 genotype status. This dual therapy appears to be effective for hetEM and PM patients. However, high dose dual rabeprazole/amoxicillin therapy was effective even for homEM patients. Therefore, the genotyping test of CYP2C19 appears to be a clinically useful tool for the optimal dual treatment with rabeprazole plus amoxicillin.

Effect of Helicobacter pylori infection and its eradication on nutrition

To investigate the effects of Helicobacter pylori infection and eradication on nutrition.

Effect of Helicobacter pylori Infection on Gastric Juice pH

BACKGROUND How Helicobacter pylori infection affects gastric acid secretion is still unclear. METHODS Gastric juice pH, ammonia concentration in gastric juice, serum gastrin level, and grade of gastritis in accordance with the Sydney System were determined for patients with gastric ulcer (GU) and duodenal ulcer (DU) before and after treatment with lansoprazole and amoxicillin, and results were compared with those of H. pylori-negative controls. RESULTS Scores for H. pylori density, atrophy, metaplasia, and activity of gastritis in the corpus were higher in patients with GU, especially those with proximally located GU, than in those with DU. Gastric juice pH was significantly higher in GU patients than in DU patients and controls. After H. pylori eradication, gastric juice pH and serum gastrin levels in both GU and DU patients were significantly decreased to control levels. In patients without eradication, no significant changes in these factors were observed. CONCLUSIONS These findings suggest that H. pylori infection and gastritis in the corpus suppress acid secretion and increase gastric juice pH, resulting in hypergastrinemia, and that eradication of H. pylori normalizes acid secretion and serum gastrin levels.

Effect of genotypic differences in interleukin-1 beta on gastric acid secretion in Japanese patients infected with helicobacter pylori

Although several studies have demonstrated a close relation between Helicobacter pylori infection and various upper gastrointestinal disorders, including gastric cancer (1–3), the specific pathophysiological explanations for this association are not known. H. pylori infection causes histological gastritis and affects gastric acid secretion (4 – 6). In patients with severe gastritis of the corpus, acid secretion is decreased markedly and the pH of gastric juice is increased (4 – 6). This decrease in acid secretion delays the elimination of bacterial toxins and products of inflammation, such as reactive oxygen radicals and nitrogen oxide (7), thereby increasing the concentration of these well-known mutagens in the stomach. Decreased acid secretion may also result in increased production of carcinogenic N-nitroso compounds because of superinfection by other bacteria or a reduction in vitamin C levels in gastric juice (8,9). An increased rate of cell turnover in inflamed mucosa further increases the opportunity for DNA damage. Moreover, decreased gastric acid secretion permits the reflux of duodenal juice, including bile, into the stomach, which can induce intestinal metaplasia, a precancerous change (10). Therefore, H. pylori–induced gastritis and subsequent acid hyposecretion may be associated with an increased risk of gastric cancer. Several inflammatory cytokines are upregulated in gastric mucosa infected with H. pylori. One of these cytokines, interleukin-1beta (IL-1 ), is important in initiating and amplifying the inflammatory responses to H. pylori infection (11). IL-1 is also a potent inhibitor of gastric acid secretion (12–14), as we have previously observed in patients infected with H. pylori (15). Increased IL-1 gene expression and severe corpus gastritis are related to increased pH of the gastric juice. In an animal model, we have recently reported that acid secretion is decreased by H. pylori infection, which is accompanied by an increase in the expression of IL-1 messenger ribonucleic acid (mRNA) in gastric mucosa as has been observed in humans. Furthermore, the decreased acid secretion in this animal model was restored to normal levels by administration of an antagonist of the IL-1 receptor (16). Therefore, IL-1 may cause the acid hyposecretion that is observed in patients with H. pylori infection and severe gastritis. Polymorphisms in the promoter region of the IL-1 gene have been associated with differences in the production of IL-1 by leukocytes in vitro (17,18). In white patients, polymorphisms in or near the interleukin gene have been associated with enhanced IL-1 production and an increased risk of gastric cancer (7). However, one of the polymorphisms (IL-1RN*2) is rare in Japan (19). Moreover, the polymorphisms in the promoter region of IL-1 (at positions 511 and 31) are closely linked and thus may not convey independent information (7,19). We studied whether gastric pH differed among the different IL-1 ( 511) genotypes in Japanese patients infected with H. pylori.

Cure of refractory duodenal ulcer and infection caused by Helicobacter pylori by high doses of omeprazole and amoxicillin in a homozygous CYP2C19 extensive metabolizer patient

A 53‐year old female patient with duodenal ulcer and Helicobacter pylori infection was treated three times with a proton pump inhibitor–based triple therapy, such as lansoprazole‐clarithromycin‐amoxicillin (INN, amoxicilline) and lansoprazole‐minocycline‐cefaclor. However, the H pylori infection was not cured. A culture test revealed that her infection was a clarithromycin‐resistant but amoxicillin‐sensitive strain of H pylori. Moreover, a polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) analysis revealed that she was a homozygous extensive metabolizer of cytochrome P450 (CYP) 2C19 (wt/wt). The usual dose of the proton pump inhibitor was therefore assumed to be insufficient for her and then she was treated with a high dose of omeprazole (120 mg/day) and amoxicillin (2250 mg/day) for 2 weeks. The H pylori infection and the ulcer lesion were then cured. One of the factors associated with success or failure of cure of H pylori infection by the proton pump inhibitor–based triple therapy appeared to be CYP2C19 genotype status. Dual treatment with a sufficient dose of a proton pump inhibitor plus amoxicillin could cure H pylori infection even after the failure to cure H pylori infection by a usual proton pump inhibitor–based triple therapy in patients with the wt/wt homozygous extensive metabolizer genotype of CYP2C19.

Involvement of cyclooxygenase-2 in hyperplastic gastritis induced by Helicobacter pylori infection in C57BL/6 mice

The hyperplastic changes observed in Helicobacter pylori‐associated gastritis have been considered to increase the risk of gastric cancer. The aim of this study was to determine whether cyclooxygenase‐2 is involved in the hyperplastic changes in mice infected with H. pylori.