Redox Homeostasis and CancerView this Special Issue
Review Article | Open Access
Pharmacological Effects and Toxicogenetic Impacts of Omeprazole: Genomic Instability and Cancer
Omeprazole (OME) is commonly used to treat gastrointestinal disorders. However, long-term use of OME can increase the risk of gastric cancer. We aimed to characterize the pharmacological effects of OME and to correlate its adverse effects and toxicogenetic risks to the genomic instability mechanisms and cancer-based on database reports. Thus, a search (till Aug 2019) was made in the PubMed, Scopus, and ScienceDirect with relevant keywords. Based on the study objective, we included 80 clinical reports, forty-six in vitro, and 76 in vivo studies. While controversial, the findings suggest that long-term use of OME (5 to 40 mg/kg) can induce genomic instability. On the other hand, OME-mediated protective effects are well reported and related to proton pump blockade and anti-inflammatory activity through an increase in gastric flow, anti-inflammatory markers (COX-2 and interleukins) and antiapoptotic markers (caspases and BCL-2), glycoprotein expression, and neutrophil infiltration reduction. The reported adverse and toxic effects, especially in clinical studies, were atrophic gastritis, cobalamin deficiencies, homeostasis disorders, polyp development, hepatotoxicity, cytotoxicity, and genotoxicity. This study highlights that OME may induce genomic instability and increase the risk of certain types of cancer. Therefore, adequate precautions should be taken, especially in its long-term therapeutic strategies and self-medication practices.
Cumulative reports suggest that a high prevalence of gastroesophageal diseases and drug-induced side effects may result in genomic instability (GI), leading to increased mutations and carcinogenesis [1–3]. Omeprazole (OME) therapy can alter the bacterial flora of the gastrointestinal tract, leading to malabsorption, enteric infections, and acute or chronic lesions in the stomach. This is due to the compensatory effect in response to decreased acid production, resulting in the destruction of the gastric glands and persistent hypergastrinemia, a denomination for atrophic gastritis .
Also, Helicobacter pylori infection and OME monotherapy can cause atrophic gastritis associated with an increased risk of mucosal dysplasia and gastric cancer . Although these events may be derived by different mechanisms, a common theme is the involvement of reactive oxygen and nitrogen species (ROS/RNS) in the human stomach and oncoprotein production such as the cytotoxin-associated gene A (CagA) .
OME, especially for long-term use, may induce DNA damage [6, 7]. Genotoxicity assays have been shown that not only OME but all prazoles (e.g., esomeprazole, lansoprazole, pantoprazole, and rabeprazole) can induce chromosomal damages [8–11]. Upon understanding the overall fact, this review aimed to sketch a current scenario on the pharmacological effects and toxicogenetic risks of OME therapy in the context of genomic instability and cancer.
2. Methodological Strategies
We conducted a systematic review of published manuscripts to determine if exposure to OME during the treatment of gastric disorders increases the risk of genomic instability and cancer. The search criteria for this study includes publications in English using the keyword “Omeprazole,” which was then paired with “genomic instability,” “genotoxicity,” “cancer,” “gastritis,” “gastric ulcer,” and “gastric/stomach cancer,” in the PubMed, Scopus, and ScienceDirect databases. We excluded irrelevant reports that are not meeting inclusion criteria, duplicated publications, and data dealing with other prazoles than OME. The data obtained are listed in Table 1. Out of the 6349 articles, only 202 met our inclusion criteria (80 clinical reports, forty-six in vitro, and 76 in vivo studies). The selected articles were read in full.
3. Characterization of Scientific Reports
We have analyzed studies based on doses, side effects, drug interactions, pharmacological effects, and toxicogenetic risks (Table 2). The therapeutic use of OME is related to the treatment of duodenal ulcers, gastric ulcers, gastric cancer, and especially to gastroesophageal pathologies (42.4%) and others (26.0%). Regarding in vitro studies, the models are more related to other pathologies (90.0%), while for in vivo, most studies are associated with the simulating gastric pathologies. Few studies emphasize the use of antioxidants during OME therapy. Also, the therapeutic use of OME in clinical, in vivo, and in vitro studies varies between 10 and 40 mg/kg, 40 mg/kg, and 40 μM to 25 mM, respectively.
#Concentration/ml. ##Dose/kg. CYP219 and CYP3AY (metabolizing enzymes). AhR: aryl hydrocarbon receptor; IL-8: interleukin 8. Chi-square test .
Regarding mechanisms of OME therapeutic action, clinical studies emphasized mechanisms of proton pump inhibition (52.6%), acid and pH control (26%), and CYP219 and CP3AY enzyme inhibition, which are involved in the processes of OME metabolism. In a similar manner, in vivo studies are also correlated to proton pump inhibition (60%) and metabolizing enzymes (14.3%), although about 18% emphasized studies related to aryl hydrocarbon receptors (AhR). Around 27% of in vitro studies are about acid and pH control, and the same percentage for AhR and proton pump.
Clinical studies on toxicogenetic effects of OME are still limited (5.3%). However, about 89.5% of them point out to oxidative risks by ROS formation, which is also observed in in vivo studies. ROS-mediated cytotoxic effects on test systems were also seen in in vitro and in vivo studies (Table 3). In spite of the scarcity of toxicogenetic studies, the OME mechanisms of action were correlated to genotoxicity by applying bivariate correlation statistics, using the Spearman correlation factor of and in nonclinical studies and and in studies with cell cultures. At clinical doses, there were correlations with genomic instability ( and ) and cytotoxicity ( and ). In studies of drug interactions, toxicity was strongly correlated with the genomic instability ( and ).
AhR: aryl hydrocarbon receptors; ROS: reactive oxygen species. Chi-square test .
4. Anatomophysiological Characteristics of the Stomach
The stomach is divided into three portions: fundus, corpus, and antrum pylorus, where the processes of digestion, absorption, and protection take place. The lubrication and protection of the gastric mucosa are maintained by enzymatic activity, during digestive process that contribute to the maintenance of acidic pH by hydrogen ion secretion . The pyloric and oxyntic glands act on the gastric mucosa. The former types are located in the antrum of the stomach and have the same cell types as the oxyntic glands, except the parietal cells that, when stimulated, release the gastrin, mainly responsible for the secretion of gastric acid . The oxyntic glands, responsible for secreting hydrochloric acid (HCl), are located in the fundus and the corpus of the stomach. They consist of somatostatin-producing D cells; main cells, responsible for the secretion of pepsinogen; enterochromaffin-like cells responsible for secretion of histamine; parietal cells, which mainly secrete HCl and intrinsic factors; and mucosal cells, responsible for the secretion of mucus and bicarbonate ions . The enterochromaffin cells are stimulated by gastrin or acetylcholine, releasing histamine, which binds to H2 receptors found in the parietal cells, stimulating the secretion of acid by the proton pump [15, 16].
Acetylcholine stimulates pepsinogen secretion by peptic cells, HCl by parietal cells, and mucus by the mucous cells . The parietal cells, present in the gastric mucosa, when stimulated, are responsible for the secretion of HCl through the H+/K+ adenosine triphosphatase (H+/K+/ATPase–proton pump) from the canalicular membrane .
4.1. Alteration of Gastric Mucosa
Gastritis is considered a superficial and inflammatory lesion that can also compromise the integrity of the stomach mucosa or duodenum and cause lesions in deeper layers, resulting in gastric ulcers  and stomach cancer . The body has preepithelial defenses against gastric lesions and protective factors such as the production of bicarbonate and mucus, nitric oxide (NO), blood flow, prostaglandins, cell regulation, growth factors, nonprotein sulfhydryl groups (SHs), and antioxidant defenses.
It is noteworthy that the lesions may be caused by alterations in the balance between protection and aggression factors to the gastric mucosa . Loss of mucosal protection, derived from the deficiency in mucus secretion and bicarbonate, favors the action of HCl . Gastric secretion, pepsin, free radicals, bile reflux, and ischemic processes are aggressive factors to the tissue . HCl and pepsin generate lesions in the gastric mucosa that destabilize the gastric barrier and cause acute inflammation .
Increased gastric HCl secretion is one of the most prominent lesion signals, and its reduction is the main strategy for preventing gastric lesions . The unbalance between harmful (HCl and pepsin) and protector agents characterizes the acute inflammatory process [24, 26]. As a consequence of chronic gastritis and stomach inflammations, peptic ulcers and gastric cancer are the most frequent pathological alterations [20, 27], especially during H. pylori infections .
4.1.2. Infection by Helicobacter pylori
H. pylori is described as a bacterium whose reservoir is the human stomach [28, 29]. It is a gram-negative bacillus, with flagella, adhesion factors, urease enzyme, cytosines, and proteases as virulence factors . H. pylori produces toxic enzymes, as well as induce the release of gastrin, leading to an increase in gastric acid secretion and pH, stimulating somatostatin release  and hypergastrinemia. H. pylori also triggers a trophic effect and hyperplasia of the enterochromaffin and parietal cells .
Infection with H. pylori may cause gastritis, gastric and peptic ulcers, and even gastric cancer . Gastric ulcer is considered one of the major public health consequences that occur due to many factors, especially the harmful activity of gastric acid and pepsin . Peptic ulcer is characterized by acid peptic lesions in the digestive tract, which result in mucosa ruptures (reaching the submucosa) that are generally found in the proximal stomach or duodenum . Gastric lesions associated with H. pylori, with exposure to acid or pepsin, are amplified and more aggressive . In vivo studies indicate that the presence of H. pylori may lead to the maintenance of chronic inflammatory responses, as well as to other pathological disorders in the stomach mucosa .
The use of nonsteroidal anti-inflammatory drugs (NSAIDs), stress, smoking, excessive alcohol consumption, and the presence of H. pylori in the gastrointestinal tract may reach the deeper layers of the muscular wall of the gastric mucosa and cause gastric ulcers [19, 36].
5. Therapies for Gastric Lesions
Proton pump inhibitors (PPIs), such as OME, are frequently used in gastric therapies [37, 38]. Other PPIs, such as lansoprazole, rabeprazole, pantoprazole, esomeprazole, and dexlansoprazole, are also used to inhibit HCl secretion . These drugs are considered efficient in suppressing gastric acidity . PPIs present chiral sulfur in their chemical structure and are activators of the AhR and inducers of CYP1A metabolism genes in human hepatoma cells and primary human hepatocytes . The product of these genes may influence the pharmacokinetics and pharmacodynamics of OME [42, 43].
PPIs activate and release sulfonamide or sulfenic acid, thus inhibit gastric acid secretion by covalently (irreversible) binding to the sulfhydryl group of cysteine in the extracellular domain of H+/K+-ATPase . A reduction in gastric acid secretion results in a faster lesion healing, depending on the dose administered .
OME is a first-line drug for inhibiting gastric acid secretion in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer, and H. pylori infection . Its mechanisms of action occur from selective and covalent activation with H+/K+-ATPase, in particular of extracellular cysteine 813, leading to potent inhibition of gastric acid secretion and triggering changes in the stomach flora . Another mechanism is by blocking the proton pump in the stomach parietal cells, activating the heat shock protein (HSP70), and the transforming growth factor beta (TGF-β) , with consequent relief of symptoms and lesion healing .
5.1. Therapeutic Effects of Omeprazole and Suggested Mechanisms
Several therapeutic effects have been suggested for OME, such as gastroprotection , antioxidant , anti-inflammatory , antinecrotic , and antiapoptotic . The mechanisms of action of these effects are presented in Figure 1.
5.1.1. Gastroprotective Effect
OME gastroprotection is attributed to its ability to block the proton pump in the parietal cells of the stomach, activating the HSP70 and the TGF-β as mentioned above . The expression of HSP70 mRNA was observed in the gastric tissue of rats pretreated with OME [54, 55]. This OME mechanism was reported for rats at doses that varied between 10 μM and 400 mg/kg, as well as 200 μM/ml in regular epithelial cell lines (MDCK) and mouse macrophage (RAW264.7) [55, 56].
In clinical studies, there is evidence of the OME gastroprotective function at doses of 5 to 40 mg/kg by mechanisms associated with interaction with H2 receptors , pH control , inhibition of CYP2C19 enzymes [42, 43], and histamine blockade . OME in in vivo studies increased prostaglandins and sulfhydryl compounds , increased expression of BAX and caspases , and AhR and CYP1A expression . These mechanisms of action may be related to other pathways that eventually cause genomic instability. Table 4 shows the gastroprotective mechanisms of OME, including its possible association with apoptosis and necrosis, as well as the risk of genomic instability.
PPIs: proton pump inhibitors; TNF-α: tumor necrosis factor-alpha.
5.1.2. Antioxidant and Anti-Inflammatory Effects
Several in vivo studies indicate antioxidant activities of OME, due to mechanisms associated with reduction of lipid peroxidation at doses of 2 to 5 mg/kg , 10 mg/kg , and 20 mg/kg . Antioxidant activities of OME were also reported considering gastric lesions in animals  and in vitro studies in epithelioid MDCK, RAW264.7 , and U-87 cells .
OME also has antioxidant activities (in vitro), by blocking hydroxyl radical (⋅OH), preventing apoptosis and necrosis , inducing nicotinamide adenine dinucleic acid (NADPH) kinase oxidoreductase production , and increasing endogenous antioxidants . In vivo and in vitro studies report inhibition of necrosis by activation of TNF-α, interleukin B , and proinflammatory cytokines . OME at 20 mg/kg presented antioxidant activity through mechanisms associated with increased superoxide dismutase (SOD) enzyme production [77, 78], as well as glutathione peroxidase (GPx) and reduced glutathione (GSH) at 30 and 40 mg/kg [51, 79]. In ethanol-induced gastritis rats, OME modulated mucosal lesions through its antioxidant and anti-inflammatory activity . However, clinical studies regarding OME antioxidant activities have not yet been reported.
There are reports of in vivo studies, in which OME had effects over increased blood flow of the gastric mucosa and expression of gastric glycoproteins  that is used as a precise and sensitive marker for the gastric mucosal status. Moreover, OME also plays a significant role as an antiacid, pepsin-resistant, and ulceration protector, which helps to protect the mucosal integrity  and reduces neutrophil infiltration .
Other mechanisms of action of OME, observed in animals and in cell cultures, relate to the anti-inflammatory marker cyclooxygenase (COX)-2  and NSAIDs, which inhibit COX-1 and COX-2 that cause gastric ulcerogenic effects  and to the increase in the neurotrophic tyrosine kinase receptor type 2 (Ntrk2) . OME also reduced TNF-α capacity (in vivo) . OME can exert its anti-inflammatory effect through increasing the anti-inflammatory cytokines and autoimmune pathologies . Proinflammatory cytokines, particularly TNF-α and nuclear factor kappa B (NF-κB), are inducers of apoptosis . NF-κB pathway is correlated to gastric lesions in response to TNF-α and IL-1 signaling [77, 87]. TNF-α is involved in inflammatory induction, lesion, and carcinogenesis in several tissues, including the gastric mucosa .
In clinical studies, OME can also act in reducing the effects of proinflammatory markers, such as IL-1β [56, 72], monocyte chemoattractant protein-1 (MCP-1) , and IL-6 . In cell cultures, esomeprazole has anti-inflammatory activity through mechanisms associated with suppression of proinflammatory proteins, including proteins of cell adhesion molecule 1, nitric oxide synthase, TNF-α, and interleukins (e.g., IL-1β and IL-6). The anti-inflammatory activity is associated with antioxidant activity by the induction of cytoprotective proteins induced by heme oxygenase-1 (HO-1), as well as by inhibition of fibroblast proliferation . OME also has anti-inflammatory effects through reduction of E-selectin  and myeloperoxidase (MPO) , which can cause damage to proteins, lipids, and DNA through ROS formation . In summary, other OME mechanisms of action as an antioxidant and/or anti-inflammatory and its protective effects and/or risk of genomic instability, as well as toxicity, are presented in Table 5.
5.1.3. Antiapoptotic and Antinecrotic Effects
Apoptosis induction is one of the mechanisms for inducing acute gastric lesion . OME presented antiapoptotic effects (in vivo) associated with reduction of caspase 3 expression , as well as reduction of BAX  and mitochondrial calcium . Other studies indicate that OME has antiapoptotic activity in the gastric and intestinal tissues, showing reduction of lesions through antioxidant processes and anti-inflammatory activity through expression of Ntrk2 gene (inductor/inhibitor of cell proliferation)  and reduction of protein Egr1, which influences the increase of protein p53 .
Mitochondrial permeability transition pore is associated with apoptosis due to free radical production, calcium accumulation , and increase in mitochondrial ATP, which is linked to the maintenance of cellular respiration  and reduction of mitochondrial cytochrome C . OME in gastric lesion models reduced ulcerative lesions , the incidence of gastric hemorrhages , prevented visible lesions with edema, erosions, and necrosis in gastric endothelial cells [102, 103], and reduced vascular permeability . OME exerted an antinecrotic effect in rats at 10 μM and 60 mg/kg doses  by increasing the gastric mucosal barrier  and reducing the necrotic area induced by skin suspension in the animal model .
5.2. Adverse Effects of Omeprazole and Suggested Mechanisms
Figure 2 shows the adverse effects of OME. Evidences suggest that OME treatment can alter the gastrointestinal bacterial flora in response to decreased acid formation [106, 107] and increased gastrin production that causes hypergastrinemia. These events can result in gastric polyps, increased risk of bacterial infection, especially H. pylori, and gastric cancer as a consequence of the decreased somatostatin release from D cells .
Chronic therapies can induce electrolyte and cobalamin deficiency, interrupted bone homeostasis, hypergastrin, and acid secretion (rebound effect) in humans . Atrophic gastritis is characterized by the destruction of the gastric glands and persistent hypergastrinemia .
Several studies have been reported that long-term OME use in the treatment of gastritis causes anomalies in the gastric mucosa, such as parietal cell hyperplasia, dilatation of canaliculi in the stomach fundus, corpus and antrum, and projection of cytoplasmic protrusions into the canaliculus lumen . Common side effects observed in the literatures include headache, diarrhea, nausea, constipation, abdominal pain, pruritus, rebound acid hypersecretion, malabsorption, vitamin B12 deficiency, and hypotension.
Long-term use of PPIs is also associated with pathological alterations, such as protrusions of parietal cells, dilation of oxyntic glands , and development of fundic gland polyps, resulting from a trophic effect on parietal cells . PPIs induce bone fractures , enteric infections , destruction of gastric glands that induce atrophic gastritis , being capable of compromising the immunological system , and increasing the risk of morbidity and mortality of patients .
Adverse side effects subsequent to long-term OME exposure include severe hypomagnesia  and hypocalcemia associated with vomiting, nausea, diarrhea, muscle cramps, and seizures are in relatively low frequency . OME has effects against ulcerative damages induced in the gastric mucosa of rats and mice [56, 61], being able to block the proton pump in the parietal cells of the stomach  and activating HSP70 .
In summary, OME gastroprotective activities may induce various adverse effects reported in clinical studies such as diarrhea, nausea, constipation, immune deficiencies, fracture induction, vitamin B12 deficiency , allergies, respiratory infections, hypo- and hyperglycemia, and electrochemical changes . It is important to emphasize that therapeutic clinical studies highlighted toxicity due to increased liver enzymes , while in in vivo and in vitro studies, toxicity has been reported by the oxidation of thiols, sulfonamides , caspase 3, and PARP cleavage . Adverse effects of OME may be associated with apoptosis and tumor induction, immune changes, hyperplasia, inflammation, and polyp formation, which may imply in genomic instability (Table 6).
6. Toxicological Risks and Genomic Instability Induced by Omeprazole
Genetic variations induced by genomic instability are involved in the processes of initiation, progression, and resistance to therapy . In the treatment of gastrointestinal disorders, drugs are intermittently or long-term used, and genotoxic risks must be assessed [6, 7]. Toxicogenetic assessment plays an important role in human health  and many drugs can be carcinogenenic due to the mechanisms associated with genotoxicity . Thus, it is important in any drug therapy to evaluate the benefits against the risks, especially long-term drug treatment [6, 7].
Studies in animals showed that some drugs induced genotoxicity through DNA damage, as well as micronuclei formation [10, 11, 135]. OME can induce DNA damage by mechanisms involved with oxidative damage, genotoxicity, and mutagenicity (Figure 3).
6.1. Oxidative Damage
Oxidative stress is an important parameter for chemical carcinogenesis . ROS are continuously generated in cells through aerobic metabolism and exogenous sources, including drugs, pesticides, and other environmental factors . This process occurs when the amount of substances responsible for oxidative damage exceeds the capacity of the endogenous antioxidant system . As a consequence, there are alterations in the process of cell signaling, regulation, activation, apoptosis, and necrosis .
ROS can cause several types of damage in distinct biomolecules, including DNA, proteins, lipids, carbohydrates, and amino acids; cause ruptures, alterations in guanine and thymine bases, and translocations across the sister chromatids. These alterations can lead to inactivation of tumor-suppressing genes, such as TP53 and ATM; or lead to increased protooncogenes gene expression . ROS can also promote genomic instability and tumorigenesis through increased glucose metabolism and hypoxia adaptations and mutations, which contribute to the abnormal cell growth, angiogenesis, and apoptosis resistance .
There are reports that OME can amplify oxidative stress as a result of gastritis, damaging the gastric mucosa rather than accelerate its healing . Excess ROS can result in inhibition of the gastric acid pump in parietal cells that leads to the release of sulfone, sulfite, and hydroxy-OME . Effects of hyperoxia, inflammation, oxidative stress, and vascular lesions are amplified with OME administration of 25 mg/kg in rats along with the lung and alveolar vascular simplification promoted by AhR .
ROS are responsible for modifications in mitochondrial permeability , causing mutations and damage to the mitochondrial DNA and the respiratory chain [144, 145]. OME can impart cytotoxicity of hyperoxia and induce ROS in lung microvascular endothelial cells, by producing hydrogen peroxide rather than acute hyperoxic lesions (in vitro) .
6.2. Genotoxic Effects
Genomic instability caused by drugs can be associated with genotoxicity induction [6, 7, 134]. In vivo studies suggest that OME can promote DNA damage  through the formation of covalent adduct with DNA in experimental animals . Assessment of genotoxicity of chemicals, including the identification of their mechanisms of action, is important to establish distinctions among carcinogens, especially in the pharmaceutical industry . Drugs that are potentially inductors of genetic instability must have to be monitored before consumption .
CYP1A1-inducible chemicals, such as benzo [a] pyrene and 2,3,7,8-tetra-chlorodibenzo-dioxins, usually have adverse effects related to genomic instability (mutagenic, carcinogenic, and teratogenic). However, studies indicate that OME does not induce carcinogenesis, but it may amplify the effects of environmental carcinogens . Nevertheless, studies on DNA damage and chromosomes are necessary and relevant , since in silico studies showed that OME can cause genotoxicity and mutagenicity through the formation of chromosomal aberrations and micronuclei .
At the molecular level, hypo- or achlorhydria triggers the formation of N-nitrosamines, which may induce DNA damage and provoke nuclear abnormalities, such as micronuclei, pyknosis, and karyorrhexis . OME does not have a direct mutagenic effect , but DNA breaks are a result of oxidative stress  in events originated from elevated ROS levels, which cause oxidative damage to cell proteins, membrane lipids, and genetic materials (e.g., DNA, RNA) .
6.3. Toxicity of Omeprazole
To understand the mechanisms of drug toxicity, it is necessary to verify drug-drug interactions, the formation of reactive metabolites, and individual susceptibility by genetic polymorphisms in drug-metabolizing enzymes . Gastric lesions are characterized by increased production of ⋅OH and protein oxidation, especially in gastric ulcers , which are related to lesion severity , producing highly toxic lipid derivatives that may modify cell function and even cell death .
OME induces hepatotoxicity in pregnant women, as observed by the reduction of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes . Hepatotoxic and nephrotoxic effects, thrombocytopenia, acute interstitial nephritis, anaphylactic reactions, gynecomastia, and impotence have been seen in the long-term OME use . Several mechanisms are involved in drug hepatotoxicity; among those is the disassembly of actin fibrils that may result in cell lysis by changes in membrane transport pumps, as well as apoptosis by activation of the TNF-α . Hepatic toxicity leads to hepatic lesions that disappear after discontinuation of the drug .
The PPIs can induce cytotoxicity through autophagic mechanisms, such as alterations in pH homeostasis . OME presented cytotoxic effects in marine microalgae Tetraselmis sp. through hyperpolarization of cytoplasm and mitochondrial membranes, as well as by cell acidification and ROS generation . Moreover, OME exerted toxic and cytotoxic effects in rabbit gastric gland cells that were attributed to oxidative processes .
More recent studies indicate that OME has antitumor activity against multiple myeloma as a single agent, and associated with chemotherapy, due to its cytotoxic activity as an apoptosis inductor, independently of caspases . OME presented antitumor effects in association with chemotherapy in rectal cancer patients, including reducing the side effects of the treatment . These effects were also observed in fibrosarcoma and colon cancer cells, suggesting that its use associated with anticancer drugs can be a promising therapy against malignant tumors .
Studies report that OME presents synergistic effects in rectal cancer chemotherapies . Several mechanisms are proposed for the antitumor effect of Na+/K+ pump inhibitors , such as cell death stimulators via caspases, apoptosis inductors [163–166], an inhibitor of the V-ATPase activity, and turn tumors chemosensitive .
Antitumoral effects of OME were also described in studies with several cancer cell lines, including Heya8-MDR, SKOV3-TR, ES-2, and RMG-1; colon carcinoma cells (320WT and 320MUT) , neuroblastoma cells (SH-SY5Y), human microglia (THP), myeloma RPMI8226, U266, human gastric cancer (HGC-27), glioblastoma (U-87), human colon cancer (HCT-116 and HCA-7) cells, and Jurkat T lymphocytes at concentrations between 10 and 106 μM [169, 170].
In xenographic model of colon carcinoma and colon cells, antitumoral effects were also observed through increase expression of immediate early response gene X-1 (IEX-1), a stress-sensitive gene [171–173]. Other mechanisms have been suggested for the OME antitumor effect, such as reduction of Bcl-2 [174–176], Bcl-xL, and survivin , as well as reduction of other antiapoptotic proteins [177, 178].
In human gastric cancer cells (HGC-27) and polymorphonuclear neutrophils, OME exerted an antitumoral effect through increase in caspase 3 , apoptotic proteins , and cleavage of poly [ADP-ribose] polymerase 1 (PARP-1) [124, 169, 170]; OME was cytotoxic in colon cells through increased gastrin secretion and increasing expression of IEX-1. Moreover, OME showed antitumor effects in different carcinomas [172, 173] through mechanisms associated with reduction of Bcl-2 and Bcl-xL expression  and in chemoresistant cells (HeyA8-MDR, SKOV3-TR) in association with the anticancer drug paclitaxel .
In relation to genotoxicity in clinical studies, it has been reported for clastogenic effects and oxidative stress mechanisms  and hydroxylation induction and sulfoxidation in OME doses of 20 to 40 mg/kg . Sulfonamide metabolites have also been reported as mechanisms for genotoxicity in in vivo studies . Additionally, there are other mechanisms associated with DNA damage, including ornithine decarboxylase induction as a marker of cell proliferation , micronuclei induction , transcriptional changes , hyperplasia, hypertrophy, and other cellular alterations (Narimar et al., 2009).
OME antitumor effects in clinical studies are rare, but some have shown synergistic effects with antitumor drugs on modulating tumor acidity and apoptosis . In in vitro studies, antitumor mechanisms have been related to expression of V-ATPase , inhibition of miR203-3p , and downregulation of metastatic CXCR4 proteins  and miRNAs . In summary, other mechanisms indicative of genotoxicity, toxicity, and cytotoxicity of OME are shown in Table 7.
7. Carcinogenic Effects of Omeprazole
Severe pathological alterations on the stomach mucosa can lead to peptic ulcer and gastric cancer , especially due to complications with H. pylori infection and exposure to acid and pepsin [46, 107]. Gastric cancer is the 15th leading cause of death by cancer, more frequent in men and mostly influenced by age, diet, and stomach diseases, including H. pylori infection .
Studies are still controversial, but H. pylori can be associated with gastric carcinoma by mechanisms related to increased ROS/RNS and oncoprotein formation . Gastric pathologies are commonly related to increased levels of gastrin [195, 196]. Atrophic gastritis, resulting from monotherapy with OME in the context of H. pylori infection, has been associated with an increased risk of mucosa dysplasia and gastric cancer .
Carcinogenicity studies are preliminary to the approval and commercialization of pharmaceutical products, including cytogenetic in vivo and in vitro assays [197–199]. Brambilla and his colleagues report that, out of 535 medications, 279 showed positive results for carcinogenicity in animal tests. Thus, the indication of drugs should consider the risk/benefit in relation to the carcinogenicity and should prioritize new therapeutic intervention strategies [6–11, 200].
Studies have shown that after chronic gastritis, atrophy, intestinal metaplasia, and dysplasia, there are increased risks for gastric cancer [27, 57], especially with H. pylori infection . Esomeprazole can induce acid suppression, leading to indigestion and amplifying risks of bacterial infections that generate atrophic gastritis [108, 202].
Long-term use of OME may relate to the cell proliferation and carcinoid tumors . Menegasse et al.  concluded that proliferative changes of the oxyntic mucosa occur in individuals with chronic use of PPIs, with statistical significance in association with age and proliferative cell alterations . Several studies reported that acid-suppressing drugs increase risks of polyp formation and/or gastric cancer due to nitrosamine production and hypergastrinemia. Decreased gastric acidity, due to gastric atrophy or to hypochloridria, may favor bacterial colonization, increasing the cancer risk . OME (20 mg) induces gastric hyperplasia and polyps that increase with therapy and regress with discontinuation, independently of H. pylori infection .
Also, studies report that OME reacts with DNA and induces cancer in rodents . OME, at high dose (30 mg/kg), was shown to induce carcinogenesis in the anterior stomach by influencing the levels of acid phosphatase (ACP) and N-acetyl-β-D-glucosaminidase (NAG) in the serum and spleen . Other evidence showed that OME can induce hypergastrinemia and colorectal tumors .
PPIs are associated with H. pylori-induced chronic atrophic gastritis, metaplasia, and carcinoma . Atrophic gastritis usually happens during monotherapies with OME, possibly resulting in dysplasia and gastric cancer .
In summary, other mechanisms of OME activity may also include carcinogenic risks due to its effects of hypergastrinemia and metaplasia . Other mechanisms are also pointed out in in vivo studies such as ROS induction, oxidation of 8-DHD6 [212, 213], premalignant lesions , cell cycle alterations, genotoxicity, hyperplasia, and inhibition of liposomal hydrolases . Several studies indicative of OME-mediated carcinogenicity are summarized in Table 8.
Studies on the mechanisms of action of OME are still controversial. As a gastroprotectant agent, it blocks proton pump, activates HSP70 proteins and TGF-β, exerts antioxidant activity, reduces lipid peroxidation, and activates expression of antioxidant defenses, without differentiation of doses and/or concentrations. Additionally, in in vitro and in vivo studies, anti-inflammatory effects of OME have been related to increased gastric flow, increased anti-inflammatory markers (COX-2, IL-10A, and IL-6), and antiapoptotic activity by reducing caspase 3, Bcl-2, mitochondrial calcium, and expression of NTRK2 and GGR1 genes. However, OME adverse effects, especially in vivo, such as changes in bacterial flora, enteric infections, gastric gland destruction, polyp formation, hypomagnesia, hypocalcemia, hyperplasia, intestinal metaplasia, electrolyte deficiency, and immunological component changes, may relate to the consequences of genomic instability. In summary, besides the gastroprotective effects, the adverse effects of OME may be due to its DNA damage capacity by inducing oxidative stress, apoptosis and necrosis, immunological alterations, cell proliferation, autophagy, and tumors.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
We are thankful to the Federal University of Piauí and PPSUS/FAPEPI for the financial support.
- A. D. Asatryan and N. L. Komarova, “Evolution of genetic instability in heterogeneous tumors,” Journal of Theoretical Biology, vol. 396, pp. 1–12, 2016.
- R. A. Burrell and C. Swanton, “Tumour heterogeneity and the evolution of polyclonal drug resistance,” Molecular Oncology, vol. 8, no. 6, pp. 1095–1111, 2014.
- L. R. Ferguson, H. Chen, A. R. Collins et al., “Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition,” Seminars in Cancer Biology, vol. 35, pp. S5–S24, 2015.
- J. E. Kohler, A. L. Blass, J. Liu, K. Tai, and D. I. Soybel, “Antioxidant pre-treatment prevents omeprazole-induced toxicity in an in vitro model of infectious gastritis,” Free Radical Biology and Medicine, vol. 49, no. 5, pp. 786–791, 2010.
- R. Wadhwa, S. Song, J. S. Lee, Y. Yao, Q. Wei, and J. A. Ajani, “Gastric cancer—molecular and clinical dimensions,” Nature Reviews Clinical Oncology, vol. 10, no. 11, pp. 643–655, 2013.
- N. Downes and J. Foster, “Regulatory forum opinion piece: carcinogen risk assessment: the move from screens to science,” Toxicologic Pathology, vol. 43, no. 8, pp. 1064–1073, 2015.
- H. G. Neumann, “Risk assessment of chemical carcinogens and thresholds,” Critical Reviews in Toxicology, vol. 39, no. 6, pp. 449–461, 2009.
- G. Brambilla, F. Mattioli, and A. Martelli, “Genotoxic and carcinogenic effects of gastrointestinal drugs,” Mutagenesis, vol. 25, no. 4, pp. 315–326, 2010.
- G. Brambilla, F. Mattioli, L. Robbiano, and A. Martelli, “Genotoxicity and carcinogenicity testing of pharmaceuticals: correlations between induction of DNA lesions and carcinogenic activity,” Mutation Research/Reviews in Mutation Research, vol. 705, no. 1, pp. 20–39, 2010.
- G. Brambilla, F. Mattioli, L. Robbiano, and A. Martelli, “Update of carcinogenicity studies in animals and humans of 535 marketed pharmaceuticals,” Mutation Research/Reviews in Mutation Research, vol. 750, no. 1, pp. 1–51, 2012.
- G. Brambilla, F. Mattioli, L. Robbiano, and A. Martelli, “Studies on genotoxicity and carcinogenicity of antibacterial, antiviral, antimalarial and antifungal drugs,” Mutagenesis, vol. 27, no. 4, pp. 387–413, 2012.
- J. Feher, Quantitative human physiology: an introduction, Academic Press, 2012.
- K. S. Jain, A. K. Shah, J. Bariwal et al., “Recent advances in proton pump inhibitors and management of acid-peptic disorders,” Bioorganic and Medicinal Chemistry, vol. 15, no. 3, pp. 1181–1205, 2007.
- M. J. Ferrua and R. P. Singh, “Modeling the fluid dynamics in a human stomach to gain insight of food digestion,” Journal of Food Science, vol. 75, no. 7, pp. R151–R162, 2010.
- R. Kenneth and M. D. Mcquaid, “Fármacos usados no tratamento de doenças gastrintesti-nais,” in Farmacologia básica e clínica, B. G. Katzung, S. B. Masters, and A. J. Trevor, Eds., pp. 1081–1092, AMGH, Porto Alegre, 12 edition, 2014.
- J. L. Wallace and K. A. Sharkey, “Farmacoterapia da acidez gástrica, úlcera pépticas e doença do refluxo gastroesofágico,” in As bases farmacológicas da terapêutica de Goodman & Gil-man, L. L. Brunton, B. A. Chabner, and B. C. Knolmann, Eds., pp. 1309–1321, AMGH, Porto Alegre, 12 edition, 2012.
- M. L. Schubert, “Gastric secretion,” Current Opinion in Gastroenterology, vol. 30, no. 6, pp. 578–582, 2014.
- X. Yao and J. G. Forte, “Cell biology of acid secretion by the parietal cell,” Annual Review of Physiology, vol. 65, no. 1, pp. 103–131, 2003.
- C. Y. Hong, S. Y. Lee, S. H. Ryu, S. S. Lee, and M. Kim, “Whole-Genome De Novo Sequencing of the lignin-degrading wood rot Fungus Phanerochaete chrysosporium (ATCC 20696),” Genome Announcements, vol. 5, no. 32, 2017.
- N. Dias, P. Santos, M. Pinto et al., “Análise de prontuários de pacientes com gastrite em um hospital na região oeste ii do estado de Goiás,” Revista Eletrônica Faculdade Montes Belos, vol. 8, no. 1, pp. 1–9, 2015.
- V. K. Bansal and R. K. Goel, “Gastroprotective effect of Acacia nilotica young seedless pod extract: Role of polyphenolic constituents,” Asian Pacific Journal of Tropical Medicine, vol. 5, no. 7, pp. 523–528, 2012.
- K. H. Song, S. R. Woo, J. Y. Chung et al., “REP1 inhibits FOXO3-mediated apoptosis to promote cancer cell survival,” Cell Death & Disease, vol. 8, no. 1, article e2536, 2017.
- T. Brzozowski, A. Ptak-Belowska, S. Kwiecien et al., “Novel concept in the mechanism of injury and protection of gastric mucosa: role of renin-angiotensin system and active metabolites of angiotensin,” Current Medicinal Chemistry, vol. 19, no. 1, pp. 55–62, 2012.
- R. Ballweg, F. Schozer, K. Elliott et al., “Multiscale positive feedbacks contribute to unidirectional gastric disease progression induced by Helicobacter pylori infection,” BMC Systems Biology, vol. 11, no. 1, 2017.
- A. H. Willemijntje and J. P. Pankaj, “Agents used for control of gastric acidity and treatment of peptic ulcers and gastroesophageal reflux disease,” in The Pharmacological Basis of Therapeutics, G. H. Joel and E. L. Lee, Eds., pp. 1010-1011, McGraw-Hill Medical Publishing Division, Britain, 2001.
- P. Malfertheiner, F. K. L. Chan, and K. E. L. Mccoll, “Peptic ulcer disease,” The Lancet, vol. 374, no. 9699, pp. 1449–1461, 2009.
- D. Y. Graham, “History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer,” World Journal of Gastroenterology: WJG, vol. 20, no. 18, pp. 5191–5204, 2014.
- V. D.'. A. Cartágenes, L. C. Martins, L. M. Carneiro, K. A. d. S. Barile, and T. C. Corvelo, “Helicobacter pylori em crianças e associação de cepas CagA na transmissão mãe-filho na Amazônia brasileira,” Revista da Sociedade Brasileira de Medicina Tropical, vol. 42, no. 3, pp. 298–302, 2009.
- K. C. Machado, G. L. S. Oliveira, É. B. V. de Sousa et al., “Spectroscopic studies on the in vitro antioxidant capacity of isopentyl ferulate,” Chemico-Biological Interactions, vol. 225, pp. 47–53, 2015.
- S. J. Konturek, P. C. Konturek, T. Brzozowski, J. W. Konturek, and W. W. Pawlik, “From nerves and hormones to bacteria in the stomach; Nobel prize for achievements in gastrology during last century,” Journal of Physiology and Pharmacology, vol. 56, no. 4, pp. 507–530, 2005.
- R. Fiocca, L. Mastracci, S. E. Attwood et al., “Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up in the LOTUS trial,” Alimentary Pharmacology & Therapeutics, vol. 36, no. 10, pp. 959–971, 2012.
- I. Polanco Allué, “Microbiota y enfermedades gastrointestinales,” Anales de Pediatría (English Edition), vol. 83, no. 6, pp. 443.e1–443.e5, 2015.
- M. Kalayci, M. A. Kocdor, T. Kuloglu et al., “Comparison of the therapeutic effects of sildenafil citrate, heparin and neuropeptides in a rat model of acetic acid-induced gastric ulcer,” Life Sciences, vol. 186, pp. 102–110, 2017.
- A. Lanas and F. K. L. Chan, “Peptic ulcer disease,” The Lancet, vol. 390, no. 10094, pp. 613–624, 2017.
- E. Mnich, M. Kowalewicz-Kulbat, P. Sicińska et al., “Impact of Helicobacter pylori on the healing process of the gastric barrier,” World Journal of Gastroenterology, vol. 22, no. 33, pp. 7536–7558, 2016.
- H. B. Pandya, H. H. Agravat, and J. S. Patel, “Prevalence of specific Helicobacter Pylori CagA, vacA, iceA, ureC genotypes and its clinical relevance in the patients with acid-peptic diseases,” Journal of Clinical and Diagnostic Research, vol. 11, no. 8, pp. 23–26, 2017.
- G. Numico, V. Fusco, P. Franco, and F. Roila, “Proton pump inhibitors in cancer patients: how useful they are? A review of the most common indications for their use,” Critical Reviews In Oncology/hematology, vol. 111, pp. 144–151, 2017.
- V. Savarino, P. Dulbecco, N. de Bortoli, A. Ottonello, and E. Savarino, “The appropriate use of proton pump inhibitors (PPIs): need for a reappraisal,” European Journal Of Internal Medicine, vol. 37, pp. 19–24, 2017.
- A. Minalyan, J. N. Benhammou, A. Artashesyan, M. S. Lewis, and J. R. Pise-Gna, “Autoimmune atrophic gastritis: current perspectives,” Clinical and Experimental Gastroenterology, vol. 10, pp. 19–27, 2017.
- M. L. Schubert and D. A. Peura, “Control of gastric acid secretion in health and disease,” Gastroenterology, vol. 134, no. 7, pp. 1842–1860, 2008.
- A. Novotna, A. Srovnalova, M. Svecarova, M. Korhonova, I. Bartonkova, and Z. Dvorak, “Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines,” PLoS One, vol. 9, no. 6, article e98711, 2014.
- S. Park, Y. J. Hyun, Y. R. Kim et al., “Effects of CYP2C19 genetic polymorphisms on PK/PD responses of omeprazole in Korean healthy volunteers,” Journal of Korean Medical Science, vol. 32, no. 5, pp. 729–736, 2017.
- Y. M. Hu, J. M. Xu, Q. Mei, X. H. Xu, and S. Y. Xu, “Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotype in healthy Chinese subjects,” Acta Pharmacologica Sinica, vol. 26, no. 3, pp. 384–388, 2005.
- W. A. Hoogerwerf and P. J. Pasricha, “Pharmacotherapy of gastric acidity, peptic ulcers and gastroesophageal reflux disease,” in The Pharmacological Basis of Therapeutics, A. G. Goodman, Ed., pp. 967–981, Mc Graw Hill, 11 edition, 2006.
- X. Wang and S. Li, “Protein mislocalization: mechanisms, functions and clinical applications in cancer,” Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, vol. 1846, no. 1, pp. 13–25, 2014.
- A. Novotna, M. Korhonova, I. Bartonkova et al., “Enantiospecific effects of ketoconazole on aryl hydrocarbon receptor,” PLoS One, vol. 9, no. 7, article e101832, 2014.
- H. Holguín, M. Ceballos, and P. Amariles, “Clinical relevance of clopidogrel and omeprazole interaction: systematic review,” Revista Colombiana de Cardiología, vol. 19, no. 1, pp. 25–32, 2012.
- E. Lahner, G. Galli, G. Esposito, E. Pilozzi, V. D. Corleto, and B. Annibale, “Updated features associated with type 1 gastric carcinoids patients: a single-center study,” Scandinavian Journal of Gastroenterology, vol. 49, no. 12, pp. 1447–1455, 2014.
- A. Muthuraman and S. Sood, “Antisecretory, antioxidative and antiapoptotic effects of montelukast on pyloric ligation and water immersion stress induced peptic ulcer in rat,” Pros-taglandins, Leukotrienes and Essential Fatty Acids, vol. 83, no. 1, pp. 55–60, 2010.
- N. E. El-Ashmawy, E. G. Khedr, H. A. El-Bahrawy, and H. M. Selim, “Nebivolol prevents indomethacin-induced gastric ulcer in rats,” Journal of Immunotoxicology, vol. 13, no. 4, pp. 580–589, 2016.
- S. B. Almasaudi, N. A. el-Shitany, A. T. Abbas et al., “Antioxidant, anti-inflammatory, and antiulcer potential of manuka honey against gastric ulcer in rats,” Oxidative Medicine and Cellular Longevity, vol. 2016, Article ID 3643824, 10 pages, 2016.
- C. Blandizzi, G. Gherardi, C. Marveggio, G. Natale, D. Carignani, and M. del Tacca, “Mechanisms of protection by omeprazole against experimental gastric mucosal damage in rats,” Digestion, vol. 56, no. 3, pp. 220–229, 1995.
- R. N. El-Naga, “Apocynin protects against ethanol-induced gastric ulcer in rats by attenuating the upregulation of NADPH oxidases 1 and 4,” Chemico-Biological Interactions, vol. 242, pp. 317–326, 2015.
- R. Al Batran, F. Al-Bayaty, M. M. Jamil Al-Obaidi et al., “In vivo antioxidant and antiulcer activity of Parkia speciosa ethanolic leaf extract against ethanol-induced gastric ulcer in rats,” PLoS One, vol. 8, no. 5, article e64751, 2013.
- S. F. A. Albaayit, Y. Abba, R. Abdullah, and N. Abdullah, “Prophylactic effects of Clausena excavata Burum. f. leaf extract in ethanol-induced gastric ulcers,” Drug Design, Development and Therapy, vol. 10, pp. 1973–1986, 2016.
- M. Mahmoud-Awny, A. S. Attia, M. F. Abd-Ellah, and H. S. El-Abhar, “Mangiferin mitigates gastric ulcer in ischemia/reperfused rats: involvement of PPAR-γ, NF-κB and Nrf 2/HO-1 signaling pathways,” PLoS One, vol. 10, no. 7, article e0132497, 2015.
- J. S. Ahn, C. S. Eom, C. Y. Jeon, and S. M. Park, “Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies,” World Journal of Gastroenterology, vol. 19, no. 16, pp. 2560–2568, 2013.
- W. Asghar, E. Pittman, and F. Jamali, “Comparative efficacy of esomeprazole and omeprazole: racemate to single enantiomer switch,” DARU Journal of Pharmaceutical Sciences, vol. 23, no. 1, p. 50, 2015.
- S. Kajiura, A. Hosokawa, A. Ueda et al., “Effective healing of endoscopic submucosal dissection-induced ulcers by a single week of proton pump inhibitor treatment: a retrospective study,” BMC Research Notes, vol. 8, no. 1, p. 150, 2015.
- C. Blandizzi, G. Natale, G. Gherardi et al., “Gastroprotective effects of pantoprazole against experimental mucosal damage,” Fundamental & Clinical Pharmacology, vol. 14, no. 2, pp. 89–99, 2000.
- F. Zhang, L. Wang, J. J. Wang, P. F. Luo, X. T. Wang, and Z. F. Xia, “The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities,” Scientific Reports, vol. 6, no. 1, article 24166, 2016.
- T. Kuramoto, E. Umegaki, S. Nouda et al., “Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study,” BMC Gastroenterology, vol. 13, no. 1, p. 85, 2013.
- D. N. Bateman, D. Colin-Jones, S. Hartz et al., “Mortality study of 18 000 patients treated with omeprazole,” Gut, vol. 52, no. 7, pp. 942–946, 2003.
- Y. Choi, H. Han, D. Shin, K. S. Lim, and K. S. Yu, “Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers,” Drug Design, Development and Therapy, vol. 9, pp. 4127–4135, 2015.
- A. Nagahara, T. Suzuki, N. Nagata et al., “A multicentre randomised trial to compare the efficacy of omeprazole versus rabeprazole in early symptom relief in patients with reflux esophagitis,” Journal of Gastroenterology, vol. 49, no. 12, pp. 1536–1547, 2014.
- T. Nishida, M. Tsujii, H. Tanimura et al., “Comparative study of esomeprazole and lansoprazole in triple therapy for eradication of Helicobacter pylori in Japan,” World Journal of Gastroenterology: WJG, vol. 20, no. 15, pp. 4362–4369, 2014.
- K. Birkmann, H. K. Junge, E. Maischberger, M. Wehrli Eser, and C. C. Schwarzwald, “Efficacy of omeprazole powder paste or enteric-coated formulation in healing of gastric ulcers in horses,” Journal of Veterinary Internal Medicine, vol. 28, no. 3, pp. 925–933, 2014.
- M. Y. Ibrahim, N. M. Hashim, S. M. Dhiyaaldeen et al., “Acute toxicity and gastroprotection studies of a new Schiff base derived manganese (II) complex against HCl/ethanol-induced gastric ulcerations in rats,” Scientific Reports, vol. 6, no. 1, article 26819, 2016.
- W. Gao, H.-Y. Li, L.-X. Wang et al., “Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats,” Asian Pacific Journal of Tropical Medicine, vol. 7, no. 5, pp. 402–406, 2014.
- Y. J. Kim, J. S. Lee, K. S. Hong, J. W. Chung, J. H. Kim, and K. B. Hahm, “Novel application of proton pump inhibitor for the prevention of colitis-induced colorectal carcinogenesis beyond acid suppression,” Cancer Prevention Research, vol. 3, no. 8, pp. 963–974, 2010.
- S. Puiac, X. Sem, A. Negrea, and M. Rhen, “Small-molecular virulence inhibitors show divergent and immunomodulatory effects in infection models of Salmonella enterica serovar Typhimurium,” International Journal of Antimicrobial Agents, vol. 38, no. 5, pp. 409–416, 2011.
- S. K. Chanchal, U. B. Mahajan, S. Siddharth et al., “In vivo and in vitro protective effects of omeprazole against neuropathic pain,” Scientific Reports, vol. 6, no. 1, pp. 1–10, 2016.
- K. Biswas, U. Bandyopadhyay, I. Chattopadhyay, A. Varadaraj, E. Ali, and R. K. Banerjee, “A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical,” Journal of Biological Chemistry, vol. 278, no. 13, pp. 10993–11001, 2003.
- A. Patel, S. Zhang, A. K. Shrestha, P. Maturu, B. Moorthy, and B. Shivanna, “Omeprazole induces heme oxygenase-1 in fetal human pulmonary microvascular endothelial cells via hydrogen peroxide-independent Nrf2 signaling pathway,” Toxicology and Applied Pharmacology, vol. 311, pp. 26–33, 2016.
- E. Balza, P. Piccioli, S. Carta et al., “Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance,” Cell Death & Disease, vol. 7, no. 7, article e2304, 2016.
- S. Hashioka, A. Klegeris, and P. L. Mcgeer, “Proton pump inhibitors exert anti-inflammatory effects and decrease human microglial and monocytic THP-1 cell neurotoxicity,” Experimental Neurology, vol. 217, no. 1, pp. 177–183, 2009.
- J.-W. Song, C.-S. Seo, T.-I. Kim et al., “Protective effects of manassantin A against ethanol-induced gastric injury in rats,” Biological and Pharmaceutical Bulletin, vol. 39, no. 2, pp. 221–229, 2016.
- H. Zheng, Y. Chen, J. Zhang et al., “Evaluation of protective effects of costunolide and dehydrocostuslactone on ethanol-induced gastric ulcer in mice based on multi-pathway regulation,” Chemico-Biological Interactions, vol. 250, pp. 68–77, 2016.
- A. T. Shimoyama, J. R. Santin, I. D. Machado et al., “Antiulcerogenic activity of chlorogenic acid in different models of gastric ulcer,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 386, no. 1, pp. 5–14, 2013.
- K. Kengkoom, N. Tirawanchai, W. Angkhasirisap, and S. Ampawong, “Omeprazole preserves the RER in chief cells and enhances re‑epithelialization of parietal cells with SOD and AQP‑4 up‑regulation in ethanol‑induced gastritis rats,” Experimental and Therapeutic Medicine, vol. 14, no. 6, pp. 5871–5880, 2017.
- Z. Fang, J. Tang, Y. Bai et al., “Plasma levels of microRNA-24, microRNA-320a, and microRNA-423-5p are potential biomarkers for colorectal carcinoma,” Journal of Experimental & Clinical Cancer Research, vol. 34, no. 1, p. 86, 2015.
- D. I. Hamdan, M. F. Mahmoud, M. Wink, and A. M. El-Shazly, “Effect of hesperidin and neohesperidin from bittersweet orange (Citrus aurantium var. bigaradia) peel on indomethacin-induced peptic ulcers in rats,” Environmental Toxicology and Pharmacology, vol. 37, no. 3, pp. 907–915, 2014.
- C. Nassenstein, S. Kerzel, and A. Braun, “Neurotrophins and neurotrophin receptors in allergic asthma,” Progress in Brain Research, vol. 146, pp. 347–367, 2004.
- S. Mao, G. Yang, W. Li et al., “Gastroprotective effects of astragaloside IV against acute gastric lesion in rats,” PLoS One, vol. 11, no. 2, p. e0148146, 2016.
- R. Sabat, G. Grütz, K. Warszawska et al., “Biology of interleukin-10,” Cytokine & Growth Factor Reviews, vol. 21, no. 5, pp. 331–344, 2010.
- T. Lawrence, “The nuclear factor NF-κB pathway in inflammation,” Cold Spring Harbor perspectives in biology, vol. 1, no. 6, 2009.
- J. Wang, T. Zhang, L. Zhu, C. Ma, and S. Wang, “Anti-ulcerogenic effect of Zuojin Pill against ethanol-induced acute gastric lesion in animal models,” Journal of Ethnopharmacology, vol. 173, pp. 459–467, 2015.
- B. K. Choo and S. S. Roh, “Berberine protects against esophageal mucosal damage in reflux esophagitis by suppressing proinflammatory cytokines,” Experimental and Therapeutic Medicine, vol. 6, no. 3, pp. 663–670, 2013.
- Y. T. Ghebremariam, J. P. Cooke, W. Gerhart et al., “Pleiotropic effect of the proton pump inhibitor esomeprazole leading to suppression of lung inflammation and fibrosis.,” Journal of Translational Medicine, vol. 13, no. 1, pp. 1–20, 2015.
- Z. Liu, Y. Luo, Y. Cheng et al., “Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats,” Experimental Biology and Medicine, vol. 241, no. 8, pp. 873–881, 2016.
- R. P. Laura, D. Dong, W. F. Reynolds, and R. A. Maki, “T47D cells expressing myeloperoxidase are able to process, traffic and store the mature protein in lysosomes: studies in T47D cells reveal a role for Cys319 in MPO biosynthesis that precedes its known role in intermolecular disulfide bond formation,” PLoS One, vol. 11, no. 2, article e0149391, 2016.
- J. Richter, J. Jimenez, T. Nagatomo et al., “Proton-pump inhibitor omeprazole attenuates hyperoxia induced lung injury,” Journal of Translational Medicine, vol. 14, no. 1, p. 247, 2016.
- K. L. Niece, N. K. Boyd, and K. S. Akers, “In vitro study of the variable effects of proton pump inhibitors on voriconazole,” Antimicrobial Agents and Chemotherapy, vol. 59, no. 9, pp. 5548–5554, 2015.
- E. Botelho-Nevers, S. Singh, L. Chiche, and D. Raoult, “Effect of omeprazole on vacuole size in Coxiella burnetii -infected cells,” Journal of Infection, vol. 66, no. 3, pp. 288-289, 2013.
- D. I. Lou, J. A. Hussmann, R. M. Mcbee et al., “High-throughput DNA sequencing errors are reduced by orders of magnitude using circle sequencing,” Proceedings of the National Academy of Sciences of the United States of the America, vol. 110, no. 49, pp. 19872–19877, 2013.
- A. Muthuraman, M. Ramesh, and A. Chauhan, “Mitochondrial dependent apoptosis: ameliorative effect of flunarizine on ischemia–reperfusion of celiac artery-induced gastric lesions in the rat,” Digestive Diseases and Sciences, vol. 56, no. 8, pp. 2244–2251, 2011.
- K. G. Nørsett, A. Laegreid, M. Langaas et al., “Molecular characterization of rat gastric mucosal response to potent acid inhibition,” Physiological Genomics, vol. 22, no. 1, pp. 24–32, 2005.
- S. M. Reed and D. E. Quelle, “p53 acetylation: regulation and consequences,” Cancers, vol. 7, no. 1, pp. 30–69, 2014.
- H. Jiang, C. Hou, S. Zhang et al., “Matrine upregulates the cell cycle protein E2F-1 and triggers apoptosis via the mitochondrial pathway in K562 cells,” European Journal of Pharmacology, vol. 559, no. 2-3, pp. 98–108, 2007.
- S. A. El-Maraghy, S. M. Rizk, and N. N. Shahin, “Gastroprotective effect of crocin in ethanol-induced gastric injury in rats,” Chemico-Biological Interactions, vol. 229, pp. 26–35, 2015.
- S. G. Kinsey, D. K. Nomura, S. T. O'Neal et al., “Inhibition of monoacylglycerol lipase attenuates non-steroidal anti-inflammatory drug-induced gastric hemorrhages in mice,” Journal of Pharmacology and Experimental Therapeutics, vol. 338, no. 3, pp. 795–802, 2011.
- G. Morini, D. Grandi, M. L. Arcari, and G. Bertaccini, “Gastroprotective activity of the novel proton pump inhibitor lansoprazole in the rat,” General Pharmacology: The Vascular System, vol. 26, no. 5, pp. 1021–1025, 1995.
- G. Morini, D. Grandi, M. L. Arcari, and G. Bertaccini, “Indomethacin-induced morphological changes in the rat gastric mucosa, with or without prior treatment with two proton pump inhibitors,” Alimentary Pharmacology and Therapeutics, vol. 9, no. 6, pp. 615–623, 1995.
- B. Maity, S. K. Yadav, B. S. Patro, M. Tyagi, S. K. Bandyopadhyay, and S. Chattopadhyay, “Molecular mechanism of the anti-inflammatory activity of a natural diarylnonanoid, malabaricone C,” Free Radical Biology and Medicine, vol. 52, no. 9, pp. 1680–1691, 2012.
- H. Sen, M. Oruç, V. M. Işik et al., “The effect of omeprazole usage on the viability of random pattern skin flaps in rats,” Annals of Plastic Surgery, vol. 78, no. 6, pp. e5–e9, 2017.
- L. Wannmacher, “Inibidores da bomba de prótons: indicações racionais,” Brasília, vol. 2, no. 1, 2004.
- G. R. Yanagihara, A. G. de Paiva, M. P. Neto et al., “Effects of long‐term administration of omeprazole on bone mineral density and the mechanical properties of the bone,” Revista Brasileira de Ortopedia, vol. 50, no. 2, pp. 232–238, 2015.
- S. Chubineh and J. Birk, “Proton pump inhibitors: the good, the bad, and the unwanted,” Southern Medical Journal, vol. 105, no. 11, pp. 613–618, 2012.
- E. Gould, C. Clements, A. Reed et al., “A prospective, placebo-controlled pilot evaluation of the effect of omeprazole on serum calcium, magnesium, cobalamin, gastrin concentrations, and bone in cats,” Journal of Veterinary Internal Medicine, vol. 30, no. 3, pp. 779–786, 2016.
- K. R. Kumar, R. Iqbal, E. Coss, C. Park, B. Cryer, and R. M. Genta, “Helicobacter gastritis induces changes in the oxyntic mucosa indistinguishable from the effects of proton pump inhibitors,” Human Pathology, vol. 44, no. 12, pp. 2706–2710, 2013.
- A. J. Schoenfeld and D. Grady, “Adverse effects associated with proton pump inhibitors,” JAMA Internal Medicine, vol. 176, no. 2, pp. 172–174, 2016.
- D. A. Corley, A. Kubo, W. Zhao, and C. Quesenberry, “Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients,” Gastroenterology, vol. 139, no. 1, pp. 93–101, 2010.
- J. Leonard, J. K. Marshall, and P. Moayyedi, “Systematic review of the risk of enteric infection in patients taking acid suppression,” The American Journal of Gastroenterology, vol. 102, no. 9, pp. 2047–2056, 2007.
- A. E. Arai and S. M. C. Gallerani, Uso Crônico de Fármacos Inibidores da Bomba de Prótons: Eficácia Clínica e Efeitos Adversos, Monografia (Especialização em Farma-cologia) – Centro Universitário Filadélfia–Londrina, 2011.
- W. Liu, S. S. Baker, J. Trinidad et al., “Inhibition of lysosomal enzyme activities by proton pump inhibitors.,” Journal of Gastroenterology, vol. 48, no. 12, pp. 1343–1352, 2013.
- W. M. Wong, K. C. Lai, K. F. Lam et al., “Prevalence, clinical spectrum and health care utilization of gastro-oesophageal reflux disease in a Chinese population: a population-based study,” Alimentary Pharmacology & Therapeutics, vol. 18, no. 6, pp. 595–604, 2003.
- T. Tamura, T. Sakaeda, K. Kadoyama, and Y. Okuno, “Omeprazole- and esomeprazole-associated hypomagnesaemia: data mining of the public version of the FDA Adverse Event Reporting System,” International Journal of Medical Sciences, vol. 9, no. 5, pp. 322–326, 2012.
- J. D. Mackay and P. T. Bladon, “Hypomagnesaemia due to proton-pump inhibitor therapy: a clinical case series,” QJM, vol. 103, no. 6, pp. 387–395, 2010.
- M. Abbas, L. Cumella, Y. Zhang et al., “Outcomes of laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass in patients older than 60,” Obesity Surgery, vol. 25, no. 12, pp. 2251–2256, 2015.
- J. J. Heidelbaugh, K. L. Goldberg, and J. M. Inadomi, “Adverse risks associated with proton pump inhibitors: a systematic review,” Gastroenterology & Hepatology, vol. 5, no. 10, p. 725, 2009.
- J. G. Dekoven and A. M. Yu, “Occupational airborne contact dermatitis from proton pump inhibitors,” Dermatitis, vol. 26, no. 6, pp. 287–290, 2015.
- B. Thomas, M. Mohamed, M. al Hail et al., “A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis,” Clinical Pharmacology: Advances and Applications, vol. 8, pp. 199–202, 2016.
- E. Capodicasa, P. Cornacchione, B. Natalini et al., “Omeprazole induces apoptosis in normal human polymorphonuclear leucocytes,” International Journal of Immunopathology and Pharmacology, vol. 21, no. 1, pp. 73–85, 2008.
- L. Scaringi, P. Cornacchione, E. Ayroldi et al., “Omeprazole induces apoptosis in Jurkat cells,” International journal of immunopathology and pharmacology, vol. 17, no. 3, pp. 331–342, 2004.
- S. Cardile and C. Romano, “Clinical utility of esomeprazole for treatment of gastroesophageal reflux disease in pediatric and adolescent patients,” Adolescent Health, Medicine and Therapeutics, vol. 3, pp. 27–31, 2012.
- A. El-Shenawy, M. Diab, M. Shemis et al., “Detection of Helicobacter pylori vacA, cagA and iceA1 virulence genes associated with gastric diseases in Egyptian patients,” Egyptian Journal of Medical Human Genetics, vol. 18, no. 4, pp. 365–371, 2017.
- S. Cohen, M. Bueno de Mesquita, and F. B. Mimouni, “Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review,” British Journal of Clinical Pharmacology, vol. 80, no. 2, pp. 200–208, 2015.
- R. Imai, T. Higuchi, M. Morimoto, R. Koyamada, and S. Okada, “Iron deficiency anemia due to the long-term use of a proton pump inhibitor,” Internal Medicine, vol. 57, no. 6, pp. 899–901, 2018.
- S. Miyamoto, M. Kato, K. Matsuda et al., “Gastric hyperplastic polyps associated with proton pump inhibitor use in a case without a history of Helicobacter pylori infection,” Internal Medicine, vol. 56, no. 14, pp. 1825–1829, 2017.
- A. B. R. Thomson, M. D. Sauve, N. Kassam, and H. Kamitakahara, “Safety of the long-term use of proton pump inhibitors,” World Journal of Gastroenterology, vol. 16, no. 19, pp. 2323–2330, 2010.
- S. E. Attwood, C. Ell, J. P. Galmiche et al., “Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies,” Alimentary Pharmacology & Therapeutics, vol. 41, no. 11, pp. 1162–1174, 2015.
- D. M. Fitzgerald, P. J. Hastings, and S. M. Rosenberg, “Stress-induced mutagenesis: implications in cancer and drug resistance,” Annual Review of Cancer Biology, vol. 1, no. 1, pp. 119–140, 2017.
- E. Zeiger, “Illusions of safety: antimutagens can be mutagens, and anticarcinogens can be carcinogens,” Mutation Research/Reviews in Mutation Research, vol. 543, no. 3, pp. 191–194, 2003.
- P. Lee, K. H. Vousden, and E. C. Cheung, “TIGAR, TIGAR, burning bright,” Cancer & Metabolism, vol. 2, no. 1, p. 1, 2014.
- G. O. Adeoye, C. G. Alimba, and O. B. Oyeleke, “The genotoxicity and systemic toxicity of a pharmaceutical effluent in Wistar rats may involve oxidative stress induction,” Toxicology Reports, vol. 2, pp. 1265–1272, 2015.
- T. Tsuchiya, A. Kijima, Y. Ishii et al., “Mechanisms of oxidative stress-induced in vivo mutagenicity by potassium bromate and nitrofurantoin,” Journal of Toxicologic Pathology, vol. 31, no. 3, pp. 179–188, 2018.
- G. H. Danaei and M. Karami, “Protective effect of thymoquinone against diazinon-induced hematotoxicity, genotoxicity and immunotoxicity in rats,” Environmental Toxicology and Pharmacology, vol. 55, pp. 217–222, 2017.
- L. M. Laskoski, R. L. Dittrich, C. A. A. Valadão et al., “Oxidative stress in hoof laminar tissue of horses with lethal gastrointestinal diseases,” Veterinary Immunology And Immunopathology, vol. 171, pp. 66–72, 2016.
- A. Woźniak, M. Walawender, D. Tempka et al., “In vitro genotoxicity and cytotoxicity of polydopamine-coated magnetic nanostructures,” Toxicology In Vitro, vol. 44, pp. 256–265, 2017.
- J. N. Moloney and T. G. Cotter, “ROS signalling in the biology of cancer,” Seminars in Cell & Developmental Biology, vol. 80, pp. 50–64, 2018.
- G. Brambilla and A. Martelli, “Genotoxicity and carcinogenicity studies of analgesics, anti-inflammatory drugs and antipyretics,” Pharmacological Research, vol. 60, no. 1, pp. 1–17, 2009.
- B. Shivanna, S. Zhang, A. Patel et al., “Omeprazole attenuates pulmonary aryl hydrocarbon receptor activation and potentiates hyperoxia-induced developmental lung injury in newborn mice,” Toxicological Sciences, vol. 148, no. 1, pp. 276–287, 2015.
- I. G. Kirkinezos, S. R. Bacman, D. Hernandez et al., “Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice,” Journal of Neuroscience, vol. 25, no. 1, pp. 164–172, 2005.
- A. Pey, T. Zamoum, R. Christen, P. L. Merle, and P. Furla, “Characterization of glutathione peroxidase diversity in the symbiotic sea anemone Anemonia viridis,” Biochimie, vol. 132, pp. 94–101, 2017.
- H. Sies, “Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: oxidative eustress,” Redox Biology, vol. 11, no. 1, pp. 613–619, 2017.
- A. Patel, S. Zhang, B. Moorthy, and B. Shivanna, “Omeprazole does not potentiate acute oxygen toxicity in fetal human pulmonary microvascular endothelial cells exposed to hyperoxia,” Pharmaceutica Analytica Acta, vol. 6, no. 10, 2015.
- B. Burlinson, S. H. Morriss, D. G. Gatehouse et al., “Genotoxicity studies of gastric acid inhibiting drugs,” The Lancet, vol. 335, no. 8686, pp. 419-420, 1990.
- D. H. Phillips, A. Hewer, and M. R. Osborne, “Interaction of omeprazole with DNA in rat tissues,” Mutagenesis, vol. 7, no. 4, pp. 277–283, 1992.
- S. Sharma and R. Bhonde, “Influence of nuclear blebs and micronuclei status on the growth kinetics of human mesenchymal stem cells,” Journal of Cellular Physiology, vol. 230, no. 3, pp. 657–666, 2015.
- H. S. Rosenkranz and G. Klopman, “Omeprazole: an exploration of its reported genotoxicity,” Mutagenesis, vol. 6, no. 5, pp. 381–384, 1991.
- D. Scott, M. Reuben, G. Zampighi, and G. Sachs, “Cell isolation and genotoxicity assessment in gastric mucosa,” Digestive Diseases and Sciences, vol. 35, no. 10, pp. 1217–1225, 1990.
- M. Pittaluga, A. Sgadari, I. Dimauro, B. Tavazzi, P. Parisi, and D. Caporossi, “Physical exercise and redox balance in type 2 diabetics: effects of moderate training on biomarkers of oxidative stress and DNA damage evaluated through comet assay,” Oxidative Medicine and Cellular Longevity, vol. 2015, Article ID 981242, 7 pages, 2015.
- T. A. Baillie and A. E. Rettie, “Role of Biotransformation in Drug-Induced Toxicity: Influence of Intra- and Inter-Species Differences in Drug Metabolism,” Drug Metabolism and Pharmacokinetics, vol. 26, no. 1, pp. 15–29, 2011.
- M. R. Cesário, B. S. Barros, C. Courson, D. M. A. Melo, and A. Kiennemann, “Catalytic performances of Ni-CaO-mayenite in CO2 sorption enhanced steam methane reforming,” Fuel Processing Technology, vol. 131, pp. 247–253, 2015.
- R. J. Fontana, P. H. Hayashi, J. Gu et al., “Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset,” Gastroenterology, vol. 147, no. 1, pp. 96–108.e4, 2014.
- N. Kaplowitz, “Drug-induced liver disorders,” Drug Safety, vol. 24, no. 7, pp. 483–490, 2001.
- M. L. Marino, S. Fais, M. Djavaheri-Mergny et al., “Proton pump inhibition induces autophagy as a survival mechanism following oxidative stress in human melanoma cells,” Cell Death & Disease, vol. 1, no. 10, article e87, 2010.
- M. Seoane, M. Esperanza, and A. Cid, “Cytotoxic effects of the proton pump inhibitor omeprazole on the non-target marine microalga Tetraselmis suecica,” Aquatic Toxicology, vol. 191, pp. 62–72, 2017.
- A. Canitano, E. Iessi, E. P. Spugnini, C. Federici, and S. Fais, “Proton pump inhibitors induce a caspase-independent antitumor effect against human multiple myeloma,” Cancer Letters, vol. 376, no. 2, pp. 278–283, 2016.
- J. L. Zhang, M. Liu, Q. Yang et al., “Effects of omeprazole in improving concurrent chemoradiotherapy efficacy in rectal cancer,” World Journal of Gastroenterology, vol. 23, no. 14, pp. 2575–2584, 2017.
- T. Ishiguro, R. Ishiguro, M. Ishiguro, and S. Iwai, “Co-treatment of dichloroacetate, omeprazole and tamoxifen exhibited synergistically antiproliferative effect on malignant tumors: in vivo experiments and a case report,” Hepatogastroenterology, vol. 59, no. 116, pp. 994–996, 2012.
- A. de Milito, R. Canese, M. L. Marino et al., “pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity,” International Journal of Cancer, vol. 127, no. 1, pp. 207–219, 2010.
- A. de Milito, E. Iessi, M. Logozzi et al., “Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species,” Cancer Research, vol. 67, no. 11, pp. 5408–5417, 2007.
- T. Morimura, K. Fujita, M. Akita, M. Nagashima, and A. Satomi, “The proton pump inhibitor inhibits cell growth and induces apoptosis in human hepatoblastoma,” Pediatric Surgery International, vol. 24, no. 10, pp. 1087–1094, 2008.
- A. Udelnow, A. Kreyes, S. Ellinger et al., “Omeprazole inhibits proliferation and modulates autophagy in pancreatic cancer cells,” PLoS One, vol. 6, no. 5, article e20143, 2011.
- M. Yeo, D. K. Kim, Y. B. Kim et al., “Selective induction of apoptosis with proton pump inhibitor in gastric cancer cells,” Clinical Cancer Research, vol. 10, no. 24, pp. 8687–8696, 2004.
- M. Bellone, A. Calcinotto, P. Filipazzi, A. de Milito, S. Fais, and L. Rivoltini, “The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors,” OncoImmunology, vol. 2, no. 1, article e22058, 2014.
- Y. Y. Lee, H. K. Jeon, J. E. Hong et al., “Proton pump inhibitors enhance the effects of cytotoxic agents in chemoresistant epithelial ovarian carcinoma,” Oncotarget, vol. 6, no. 33, pp. 35040–35050, 2015.
- Q. Zhang, N. Huang, J. Wang et al., “The H+/K+-ATPase inhibitory activities of Trametenolic acid B from Trametes lactinea (Berk.) Pat, and its effects on gastric cancer cells,” Fitoterapia, vol. 89, pp. 210–217, 2013.
- X. Zhang, H. Wang, L. He et al., “Using biochar for remediation of soils contaminated with heavy metals and organic pollutants,” Environmental Science and Pollution Research, vol. 20, no. 12, pp. 8472–8483, 2013.
- A. D. Kondratyev, K. N. Chung, and M. O. Jung, “Identification and characterization of a radiation-inducible glycosylated human early-response gene,” Cancer Research, vol. 56, no. 7, pp. 1498–1502, 1996.
- S. Müerköster, A. Isberner, A. Arlt et al., “Gastrin suppresses growth of CCK2 receptor expressing colon cancer cells by inducing apoptosis in vitro and in vivo,” Gastroenterology, vol. 129, no. 3, pp. 952–968, 2005.
- S. S. Müerköster, A. V. Rausch, A. Isberner et al., “The apoptosis-inducing effect of gastrin on colorectal cancer cells relates to an increased IEX-1 expression mediating NF-κB inhibition,” Oncogene, vol. 27, no. 8, pp. 1122–1134, 2008.
- T. Brzozowski, P. C. Konturek, M. Mierzwa et al., “Effect of probiotics and triple eradication therapy on the cyclooxygenase (COX)-2 expression, apoptosis, and functional gastric mucosal impairment in Helicobacter pylori-infected Mongolian gerbils,” Helicobacter, vol. 11, no. 1, pp. 10–20, 2006.
- B. Brzozowski, A. Mazur-Bialy, R. Pajdo et al., “Mechanisms by which stress affects the experimental and clinical inflammatory bowel disease (IBD): role of brain-gut axis,” Current Neuropharmacology, vol. 14, no. 8, pp. 892–900, 2016.
- J. M. Patlolla, Y. Zhang, Q. Li, V. E. Steele, and C. V. Rao, “Anti-carcinogenic properties of omeprazole against human colon cancer cells and azoxymethane-induced colonic aberrant crypt foci formation in rats,” International Journal of Oncology, vol. 40, no. 1, pp. 170–175, 2012.
- C. Deng, P. Zhang, J. Wade Harper, S. J. Elledge, and P. Leder, “Mice Lacking p21 CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control,” Cell, vol. 82, no. 4, pp. 675–684, 1995.
- M. S. Pavlyukov, N. V. Antipova, M. V. Balashova, T. V. Vinogradova, E. P. Kopantzev, and M. I. Shakhparonov, “Survivin monomer plays an essential role in apoptosis regulation,” Journal of Biological Chemistry, vol. 286, no. 26, pp. 23296–23307, 2011.
- P. Hrelia, C. Fimognari, F. Maffei, G. Brandi, G. Biasco, and G. Cantelli-Forti, “Mutagenic and clastogenic activity of gastric juice in human gastric diseases,” Mutation Research/Genetic Toxicology and Environmental Mutagenesis, vol. 514, no. 1-2, pp. 125–132, 2002.
- V. Michaud, Y. Kreutz, T. Skaar et al., “Efavirenz-mediated induction of omeprazole metabolism is CYP2C19 genotype dependent,” The Pharmacogenomics Journal, vol. 14, no. 2, pp. 151–159, 2014.
- J. Fryklund, A. K. Falknas, and H. F. Helander, “Omeprazole does not cause un-scheduled DNA synthesis in rabbit parietal cells in vitro,” Scandinavian Journal of Gastroenterology, vol. 27, no. 6, pp. 521–528, 1992.
- C. Furihata, K. Hirose, and T. Matsushima, “Genotoxicity and cell proliferative activity of omeprazole in rat stomach mucosa,” Mutation Research Letters, vol. 262, no. 1, pp. 73–76, 1991.
- Y. Hou, Q. Hu, J. Huang, and H. Xiong, “Omeprazole inhibits cell proliferation and induces G0/G1 cell cycle arrest through up-regulating miR-203a-3p expression in Barrett’s esophagus cells,” Frontiers in Pharmacology, vol. 8, p. 968, 2018.
- U. H. Jin, S. O. Lee, C. Pfent, and S. Safe, “The aryl hydrocarbon receptor ligand omeprazole inhibits breast cancer cell invasion and metastasis,” BMC Cancer, vol. 14, no. 1, p. 498, 2014.
- K. Lindner, C. Borchardt, M. Schöpp et al., “Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer,” Journal of Experimental & Clinical Cancer Research, vol. 33, no. 1, p. 73, 2014.
- S. K. Goswami, D. Wan, J. Yang et al., “Anti-ulcer efficacy of soluble epoxide hydrolase inhibitor TPPU on diclofenac-induced intestinal ulcers,” Journal of Pharmacology and Experimental Therapeutics, vol. 357, no. 3, pp. 529–536, 2016.
- J. M. Gutiérrez, S. Villar, and A. A. Plavan, “Micronucleus test in fishes as indicators of environmental quality in subestuaries of the Río de la Plata (Uruguay),” Marine Pollution Bulletin, vol. 91, no. 2, pp. 518–523, 2015.
- J. R. Graham, “Gastric polyposis: onset during long-term therapy with omeprazole,” The Medical Journal of Australia, vol. 157, no. 4, pp. 287-288, 1992.
- P. F. Haastrup, M. S. Paulsen, R. D. Christensen, J. Søndergaard, J. M. Hansen, and D. E. Jarbøl, “Medical and non-medical predictors of initiating long-term use of proton pump inhibitors: a nationwide cohort study of first-time users during a 10-year period,” Alimentary Pharmacology & Therapeutics, vol. 44, no. 1, pp. 78–87, 2016.
- T. Hagiwara, K. Mukaisho, T. Nakayama, H. Sugihara, and T. Hattori, “Long-term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma development in Mongolian gerbils infected with Helicobacter pylori,” Gut, vol. 60, no. 5, pp. 624–630, 2011.
- M. Bakhriansyah, P. C. Souverein, A. de Boer, and O. H. Klungel, “Gastrointestinal toxicity among patients taking selective COX-2 inhibitors or conventional NSAIDs, alone or combined with proton pump inhibitors: a case�control study,” Pharmacoepidemiology and Drug Safety, vol. 26, no. 10, pp. 1141–1148, 2017.
- D. Hanahan and R. A. Weinberg, “Hallmarks of cancer: the next generation,” Cell, vol. 144, no. 5, pp. 646–674, 2011.
- Y. Hu, Z. Ma, Y. He, W. Liu, Y. Su, and Z. Tang, “LNCRNA-SNHG1 contributes to gastric cancer cell proliferation by regulating DNMT1,” Biochemical and Biophysical Research Communications, vol. 491, no. 4, pp. 926–931, 2017.
- H. Suzuki and H. Mori, “World trends for H. pylori eradication therapy and gastric cancer prevention strategy by H. pylori test-and-treat,” Journal of Gastroenterology, vol. 53, no. 3, pp. 354–361, 2018.
- M. D. Burkitt, A. Varro, and D. M. Pritchard, “Importance of gastrin in the pathogenesis and treatment of gastric tumors,” World Journal of Gastroenterology, vol. 15, no. 1, pp. 1–16, 2009.
- L. Lundell, M. Vieth, F. Gibson, P. Nagy, and P. J. Kahrilas, “Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology,” Alimentary Pharmacology & Therapeutics, vol. 42, no. 6, pp. 649–663, 2015.
- CDER, Guidelines for industry. S1A. The need for long-term rodent carcinogenicity studies of pharmaceuticals, Center for Drug Evaluation and Research, Food and Drug Administration, USA, 1996.
- CDER US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Guidance for Industry. S1B. Testing for Carcinogenicity of Pharmaceuticals, Center for Drug Evaluation and Research, Food and Drug Administration, USA, 1997.
- Iarc Working Group on the Evaluation of Carcinogenic Risks to Humans, “IARC monographs on the evaluation of carcinogenic risks to humans. Ingested nitrate and nitrite, and cyanobacterial peptide toxins,” IARC monographs on the evaluation of carcinogenic risks to humans, vol. 94, 2010.
- Y. Li, X. Wen, L. Wang et al., “LncRNA ZEB1-AS1 predicts unfavorable prognosis in gastric cancer,” Surgical Oncology, vol. 26, no. 4, pp. 527–534, 2017.
- M. Kodama, K. Murakami, T. Okimoto et al., “Helicobacter pylori eradication improves gastric atrophy and intestinal metaplasia in long-term observation,” Digestion, vol. 85, no. 2, pp. 126–130, 2012.
- N. Kangwan, J. M. Park, E. H. Kim, and K. B. Hahm, “Quality of healing of gastric ulcers: natural products beyond acid suppression,” World Journal of Gastrointestinal Pathophysiology, vol. 5, no. 1, pp. 40–47, 2014.
- M. P. Braga, C. D. B. d. Silva, and A. I. H. Adams, “Inibidores da bomba de prótons: Revisão e análise farmacoeconômica,” Saúde (Santa Maria), vol. 37, no. 2, p. 19, 2011.
- V. de Souza Menegassi, L. E. A. Czeczko, L. S. G. Czeczko, S. O. Ioshii, J. C. Pisani, and O. R. Junior, “Prevalência de alterações proliferativas gástricas em pacientes com uso crônico de inibidores de bomba de prótons,” Arquivos Brasileiros de Cirurgia Digestiva, vol. 23, no. 3, pp. 145–149, 2010.
- Melbourne, Austrália Publicado em Global Family Doctor 2011, Inibidores da bomba de prótons-efeitos adversos incomuns, Disponível em, 2013, http://www.sbmfc.org.br/default.asp?siteAcao=mostraPagina&paginaId=748.
- L. Eslami and S. Nasseri-Moghaddam, “Meta-analyses: does long-term PPI use increase the risk of gastric premalignant lesions?” Archives of Iranian Medicine, vol. 16, no. 8, pp. 449–458, 2013.
- L. Huang, D. J. Qi, W. He, and A. Xu, “Omeprazole promotes carcinogenesis of fore-stomach in mice with co-stimulation of nitrosamine,” Oncotarget, vol. 8, no. 41, pp. 70332–70344, 2017.
- J. W. Freston, M. Hisada, D. A. Peura et al., “The clinical safety of long-term lansoprazole for the maintenance of healed erosive oesophagitis,” Alimentary Pharmacology & Therapeutics, vol. 29, no. 12, pp. 1249–1260, 2009.
- B. G. Schneider, M. B. Piazuelo, L. A. Sicinschi et al., “Virulence of infecting Helicobacter pylori strains and intensity of mononuclear cell infiltration are associated with levels of DNA hypermethylation in gastric mucosae,” Epigenetics, vol. 8, no. 11, pp. 1153–1161, 2014.
- M. Tsuda, M. Asaka, M. Kato et al., “Effect on Helicobacter pylori eradication therapy against gastric cancer in Japan,” Helicobacter, vol. 22, no. 5, p. e12415, 2017.
- N. Nandy, J. A. Hanson, R. G. Strickland, and D. M. McCarthy, “Solitary gastric carcinoid tumor associated with long-term use of omeprazole: a case report and review of the literature,” Digestive Diseases and Sciences, vol. 61, no. 3, pp. 708–712, 2016.
- H. Hayashi, K. Shimamoto, E. Taniai et al., “Liver tumor promoting effect of omeprazole in rats and its possible mechanism of action,” The Journal of Toxicological Sciences, vol. 37, no. 3, pp. 491–501, 2012.
- H. Hayashi, E. Taniai, R. Morita et al., “Enhanced liver tumor promotion but not liver initiation activity in rats subjected to combined administration of omeprazole and β-naphthoflavone,” The Journal of Toxicological Sciences, vol. 37, no. 5, pp. 969–985, 2012.
- H. Song, J. Zhu, and D. Lu, “Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions,” Cochrane Database of Systematic Reviews, no. 12, article CD010623, 2014.
- P. Ekström, L. Carling, P. Unge, O. Anker-Hansen, S. Sjöstedt, and H. Sellström, “Lansoprazole versus omeprazole in active duodenal ulcer:a double-blind, randomized, comparative study,” Scandinavian Journal of Gastroenterology, vol. 30, no. 3, pp. 210–215, 1995.
- T. Hagiwara, K.-i. Mukaisho, Z.-Q. Ling, H. Sugihara, and T. Hattori, “Development of pancreatic acinar cell metaplasia after successful administration of omeprazole for 6 months in rats,” Digestive Diseases and Sciences, vol. 52, no. 5, pp. 1219–1224, 2007.
- N. Vakil, “Rationale for a Helicobacter pylori test and treatment strategy in gastroesophageal reflux disease,” Gastroenterology Clinics of North America, vol. 44, no. 3, pp. 661–666, 2015.
- J. Ashby, “Consideration of CASE predictions of genotoxic carcinogenesis for omeprazole, methapyrilene and azathioprine,” Mutation Research/Environmental Mutagenesis and Related Subjects, vol. 272, no. 1, pp. 1–7, 1992.
Copyright © 2020 Márcia Fernanda Correia Jardim Paz et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.