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PubMed1986

Potential hazards of hypochlorhydria in the treatment of peptic ulcer.

The introduction of ulcer-healing drugs that do not induce hypochlorhydria--the main aim of therapy thus far--has led to the consideration of the possible disadvantages of acid secretion inhibition. Potential dangers are that micro-organisms destroyed by the normal stomach survive and proliferate in the stomach and small intestine. The incidence of gastric cancer is higher in pernicious anemia and after partial gastrectomy. It has been suggested that the intragastric bacteria may convert dietary nitrate into nitrite that may then be nitrosated to carcinogenic N-nitroso compounds. The third potential hazard is the development of stagnant loop syndrome in patients treated with H2 antagonists. In a double-blind randomised trial of colloidal bismuth subcitrate (CBS) versus cimetidine in duodenal ulcer, gastric juice was aspirated for pH measurement. There was a significant increase in the total number of bacteria isolated during cimetidine treatment (P less than 0.01) and an increase in nitrate-reducing organisms (P less than 0.05), but no change in the CBS group. It is concluded that there may be advantages in using ulcer-healing drugs that do not reduce H+ concentration.

Blind Loop Syndrome↗
PubMed1994

Dietary factors in the aetiology of diabetes.

Quite different nutrition-related environmental factors influence the development of type 1 insulin-dependent diabetes (IDDM) and type 2 non-insulin-dependent diabetes (NIDDM). IDDM is characterized by progressive beta-cell destruction which leads to complete insulin deficiency; at the time of diagnosis 80-90% of beta cells have been destroyed. In children there is epidemiological evidence that high intake of nitrites and N-nitroso compounds, early introduction of cow's milk to the diet and short duration or absence of breastfeeding increase the risk of IDDM. Studies in experimental animals suggest that cow's milk and soy proteins may be diabetogenic. There is current interest in the effects of free radical scavengers, particularly niacin and natural and synthetic antioxidants on the incidence of IDDM. These findings from ecological, animal, and human case-control studies remain to be evaluated in prospective cohort studies covering infancy and childhood and finally in human intervention trials. NIDDM is characterized by insulin resistance which is complicated by impaired insulin secretion at the time of appearance of hyperglycaemia and clinical diabetes. Its preclinical development is insidious and poorly defined, and there is little direct evidence that the same factors which influence metabolic control in clinical diabetes also affect the preclinical development of the disorder. Obesity, particularly of the abdominal type, is common in people who develop NIDDM, and weight control by appropriate diet and physical activity is probably the most important measure for preventing NIDDM. High (saturated) fat intake seems to be associated with insulin resistance, obesity and increased risk of NIDDM, and diets high in carbohydrate seem to protect from glucose intolerance and diabetes, mainly owing to their high fibre content.

Animals↗
PubMed1989

Electrochemical characteristics of nitro-heterocyclic compounds of biological interest. III. Nitroso derivative formation.

Upon electrolytic reduction of a range of nitro-aromatic complexes (including imidazoles, benzenoids, furans and pyrazoles) an associated oxidation-reduction process is observed at more positive potentials with respect to nitro group reduction when using repeat scan cyclic voltammetry. This new couple has been identified as the reversible first reduction of the nitroso derivative for chloramphenicol, by the addition of a genuine sample of nitrosochloramphenicol to the electrochemical cell. We have failed to observe formation of the new redox-active species for five 5-nitroimidazoles examined. Possible reaction schemes for nitroso formation under electrolytic reduction conditions and the importance of the nitroso redox couple with respect to the cytotoxic action of the parent drug are discussed. The applicability of nitrosochloramphenicol as a model for the behaviour of nitro-heterocycles in general is shown.

Chloramphenicol↗
PubMed1989

Spin trapping of free radicals formed during peroxidation of sarcolemmal membranes (SLM).

The generation of free radicals in a superoxide (O2-.) driven Fe+3 catalysed reactions with isolated myocytic sarcolemma using electron spin resonance was investigated. Incubation of highly purified canine myocytic sarcolemma in the presence of the spin trap, 2-methyl-2-nitrosopropane (MNP), followed by the addition of dihydroxyfurmarate (DHF) and Fe+3-ADP resulted in the generation and detection of radical adducts of this spin trap. Spin trapping of the alkyl radicals with 2-methyl-2-nitrosopropane led to the identification of methyl radical adduct following exposure to DHF/Fe+3-ADP. With sarcolemma and the alkyl nitroso compound, the only radical product trapped was the methyl radical formed by beta-scission of alkoxyl radical. The participation of hydroperoxide-derived radicals in this system verified that the decomposition of unsaturated hydroperoxy fatty acid does proceed via a free radical mechanism.

Animals↗
PubMed1997

Reaction of substituted anthracenes and a butadiene with nitric oxide: product formation determined by EPR spectroscopy.

When nitric oxide (NO), generated from nitric acid and copper, was reacted with a series of 9,10-substituted anthracenes, only 9,10-dimethylanthracene gave EPR detectable nitroxide radicals, although the expected bicyclic nitroxide arising from cheletropic NO addition across the 9,10-positions was not observed. Purity of the NO is crucial as the presence of higher oxides of nitrogen leads to radicals by hydrogen abstraction which are trapped by NO and the resultant nitroso compounds produce stable nitroxides detectable by EPR. In contrast the acyclic system, 3,4-diphenyl-2,5-dimethyl-2,4-hexadiene gives rise to an EPR spectrum consistent with cheletropic NO addition, although higher oxides of nitrogen again mediate the formation of different nitroxides.

Anthracenes↗
PubMed1986

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis.

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Electrochemical determination of N-oxidized procainamide metabolites and functional assessment of effects on murine cells in vitro.

Because of the implication of N-oxidized metabolites of procainamide in the induction of drug-related lupus, we have studied the electrochemical behavior of these metabolites and developed an electrochemical synthesis of nitrosoprocainamide. This synthesis was developed using procainamide hydroxylamine as the starting material which was oxidized to the nitroso species at an applied potential of 700 mV vs Ag/AgCl using a carbon packed bed bulk electrolysis flow cell. Conversion efficiencies of greater than 95% were achieved with this method. Subsequent studies with a chemically diverse series of biocompounds were used to investigate possible reactions between the procainamide hydroxylamine and nitroso species and these selected molecules. Only antioxidants such as cysteine, glutathione and ascorbic acid were found to react with the nitroso compound as determined by electrochemical methods, and this reaction was characterized as primarily a simple redox reaction at physiological pH. Animal studies conducted with murine spleen cells incubated with mitogens and various procainamide compounds demonstrated that the N-oxidized metabolites are the active immunopharmacologic agents.

Acecainide↗
PubMed2001

Carcinogenic potential of duodenal reflux juice from patients with long-standing postgastrectomy.

AIM: To determine whether study on the carcinogenic potential of reflux juice from patients with remote gastrectomy could clarify the inherent relationship between duodenal reflux and gastric stump cancer. METHODS: A total of 37 reflux juice samples (13 Billroth I, 24 Billroth II) were employed in the present study. A two-stage transformation assay using BALB/c 3T3 cells was carried out to test the initiating or promoting activity of these samples. RESULTS: Two of 18 (11.1%) reflux samples exerted initiating activities, whereas 9/19 (47.4%) samples enhanced the MNNG-initiating cell transformation, suggesting the duodenal reflux juice might more frequently possess the tumor-promoter activity (P = 0.029). In addition, there was no difference in initiating activities of the samples irrespective of surgical procedures (P = 0.488), while Billroth II samples exhibited stronger tumor-promoter activity than Billroth I samples (P = 0.027). Furthermore, the promoter activities were well correlated with the histological changes of the stomas (r(s) = 0.625, P = 0.004), but neither their cytotoxicities nor initiating activities had this correlation (Probabilities were 0.523 and 0.085, respectively). CONCLUSION: The duodenal reflux juice from patients with remote postgastrectomy did have carcinogenic potential, and suggested that tumor-promoting activity should principally account for the high incidence of gastric cancer in gastrectomy patients. In contrast, it is difficult to explain the high stump-cancer incidence with the N-nitroso compounds theory-a popular theory for the intact stomach carcinogenesis, and it seemed to be justified to focus chemo-prevention of this cancer on the tumor-promoting potential of reflux juice.

3T3 Cells↗
PubMedDate not supplied

In search of the cause of gastric cancer.

The purpose of this review was to describe the historical development of each epidemiology, experimental pathology, endocrinology (including vitaminology), and thermodynamics surrounding the genesis of gastric cancer in humans and non-human mammals. Epidemiological studies from other and our laboratories were unanimous in counting the intake of carbohydrate-rich and salty diet with vitamin C deficiency as the risk factor of key importance. Information from experimental pathology suggested the possible implication of some nitroso compounds in a subject with atrophic gastritis and/or in a state of vitamin C deficiency of which the establishment should have led to a perturbation of the steroid milieu of the host. In endocrinology, the association of a specific steroid disorder (depression of androgen and progestin combined with glucocorticoid excess in urine) with gastric cancer, as noted in the case-control study of this neoplasia, was reproduced in mice maintained under biased nutritional conditions. The use of scurvy-prone ODS rats was found useful in elucidating the interrelation between vitamin C and steroid metabolism. Finally, thermodynamic analysis of the data distribution of gastric cancer risk parameter of both sexes revealed the presence of an interaction between oncogene activation and tumor suppressor gene inactivation in the course of the maintenance of the positive correlation with male predominance between male gastric cancer and female gastric cancer as regards the changes of age-adjusted incidence rate (AAIR) in space. In conclusion, all of the information available in the field of gastric cancer etiology is in support of the pertinence of the steroid criminal hypothesis of gastric cancer in humans and in non-human mammals.

Animals↗
PubMed2000

Epidemiology of gastric cancer: an evaluation of available evidence.

Despite a dramatic reduction in incidence and mortality rates, gastric cancer (GC) is still one of the most common malignant neoplasias worldwide. Surgical and medical treatments have not substantially improved during the last decades, and large-scale early diagnosis programs have proven feasible in only one high-risk country, Japan. A large number of studies have indicated that salted, smoked, pickled, and preserved foods (rich in salt, nitrite, and preformed N-nitroso compounds) are associated with an increased risk of GC. In contrast, strong evidence has been provided that high consumption of fresh fruit and raw vegetables and a high intake of antioxidants are associated with a reduced risk of GC. Domestic refrigeration and reduced salt consumption are considered to play a role in explaining the decreasing temporal trend and the geographical patterns of GC. Familial factors have been suspected to play a role in GC susceptibility, and recently germ line mutations in the E-cadherin gene were identified in a few families. Evidence of a positive association between Helicobacter pylori infection and GC risk has been provided by most prospective studies that overall suggest a two- to threefold increase in risk. Randomized intervention studies on H. pylori eradication and its effects on GC predisposing conditions (atrophic gastritis and intestinal metaplasia) are in progress and represent a priority for epidemiological research in view of the potential preventive applications. Overall, it is evident that several factors (including diet, individual susceptibility and H. pylori infection) interact in a complex multifactorial process, leading over a long period of time to GC.

Causality↗
PubMed2000

Cytochrome P450 2E1 polymorphism in gastric cancer in Brazil: case-control studies of Japanese Brazilians and non-Japanese Brazilians.

Cytochrome P450 2E1 (Cyp2E1) is involved in the metabolic oxidation of carcinogenic nitroso compounds, including N-nitrosoamines. There is an RsaI polymorphism in the transcriptional regulatory region of this gene, and in vitro evidence suggests that the variant type of this polymorphic site has higher transcriptional activity but less chlorzoxazone-metabolizing activity. Interindividual differences in the metabolic capacity of Cyp2E1 are assumed to be associated with cancer susceptibility, but the results of the previous studies on the relation between Cyp2E1 RsaI polymorphism and cancer susceptibility have been inconsistent. Two case-control studies of gastric cancer in Japanese Brazilians (96 cases, 192 controls) and Brazilians not of Japanese ancestry (non-Japanese Brazilians; 236 cases, 236 controls) in São Paulo were designed to clarify the role of the Cyp2E1 RsaI genotype in susceptibility to gastric cancer after considering multifactorial environmental influences. The subjects with variant RsaI genotypes amounted to 47% (28 of 59) and 48% (64 of 133), respectively, of the Japanese cases and controls, and 6% (11 of 187) and 10% (19 of 192), respectively, of the non-Japanese cases and controls. As expected, a difference in the distributions of the two groups was observed. The odds ratio of the RsaI variant genotype of Cyp2E1 was 0.46 (95% confidence interval, 0.21-1.04) in the non-Japanese Brazilian population and 0.98 (95% confidence interval, 0.50-1.90) in the Japanese Brazilian population after adjusting for sex, age, tobacco use, and meat consumption. Additional adjustment for potential confounding factors did not change the odds ratio substantially. No significant interactions were observed between the polymorphism and environmental factors. In regard to the histological type of gastric cancer, the variant genotype was significantly more prevalent than the common genotype in Japanese subjects with diffuse type gastric cancer. Our study suggests that the Cyp2E1 RsaI polymorphism is associated with a reduced risk of gastric cancer, although how the assumed increase in Cyp2E1 expression produced by this polymorphism is related to a reduced risk of cancer remains unclear. The observations in this study are consistent with the recent observations of esophageal cancer in endemic areas of China.

Aged↗
PubMed1975

Developments in the epidemiology of stomach cancer over the past decade.

The history of stomach cancer epidemiology is reviewed. The introduction of migrant population studies in the 1960 decade that described the critical role of exposures to this disease in early life was a key event. Companion pathology studies have indicated different epidemiological patterns for 2 histological entities, intestinal and diffuse type carcinomas, and confirmed an excess of intestinal metaplasia in populations at high risk to stomach cancer. Recent results suggest that epidemiology of stomach cancer can be transformed into the epidemiology of precursor lesions, and introduction of the fiberoptic gastroscope makes technically feasible detailed studies of the relationship of precursor lesions to suspect factors, including diet, in selected geographic areas. Nitroso compounds have been identified as candidate carcinogens and the epidemiological, pathological, and chemical data display signs of internal consistency. Feeding experiments with N-methyl-N'-nitro-N-nitrosoguanidine have led to animal models that permit a coordinated epidemiological-experimental approach to stomach cancer.

Age Factors↗
PubMed1975

Induction of urinary bladder tumors in rats by administration nitrosomethyldodecylamine.

Nitrosomethyl-n-dodecylamine, a product of the reaction of dimethyl-n-dodecylamine with nitrous acid, was given to Sprague-Dawley rats by gavage in olive oil solution. Twice-weekly treatments with 12 mg of the nitrosamine for 50 weeks gave rise to 100% incidence of transitional cell carcinomas of the urinary bladder. In contrast with the tests of other N-nitroso compounds, this compound seemed to be more effective in males than in females; females died later with the tumor although the dose per unit body weight was higher in females than in males.

Animals↗
PubMed1975

Carcinogenicity of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, and its metabolites in rats.

Chronic oral administration of the antineoplastic agent, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388, DTIC), induced predominantly thymic and mammary tumors as demonstrated previously. Male and female Sprague-Dawley and female Buffalo rats were susceptible to the carcinogenicity of DTIC. A 50% incidence of mammary adenocarcinomas was induced in males within 18 weeks. Type of tumor and tumor incidence were dose dependent. Single and multiple intraperitoneal injections of DTIC did not alter organ specificity. DTIC-induced thymic lymphosarcomas and mammary adenocarcinomas were transplantable. Tissue distribution studies revealed no correlation between uptake of DTIC by a given tissue and its susceptibility to carcinogenicity. Metabolites of DTIC were tested for carcinogenic activity. Animals administered 5-diazoimidazole-4-carboxamide orally, intraperitoneally, or intragastrically developed low incidences of thymic, stomach, bladder, or mammary tumors. A low incidence of mammary tumors developed in rats fed 2-azahypoxanthine. A variety of tumors, including several ependymoblastomas, were induced in rats that received 5-aminoimidazole-4-carboxamide orally. 5-(3-Methyl-1-triazeno)imidazole-4-carboxamide (MTIC), when fed or given in single or multiple intraperitoneal injections, induced a high incidence of mammary adenofibromas and a low incidence of uterine leiomyosarcomas. Control rats had low incidences of mammary adenocarcinomas and adenofibromas after 52 weeks. These data show that the carcinogenic properties of DTIC resemble those of carcinogenic N-nitroso compounds, hydrazine, azo, and azoxy-alkanes and aryltriazenes and thus suggest similar mechanism(s) of action. These data also indicate that MTIC is involved in the induction of mammary adenofibromas and uterine leiomyosarcomas by DTIC.

Adenofibroma↗
PubMed2001

Final report on the safety assessment of Cocoyl Sarcosine, Lauroyl Sarcosine, Myristoyl Sarcosine, Oleoyl Sarcosine, Stearoyl Sarcosine, Sodium Cocoyl Sarcosinate, Sodium Lauroyl Sarcosinate, Sodium Myristoyl Sarcosinate, Ammonium Cocoyl Sarcosinate, and Ammonium Lauroyl Sarcosinate.

This safety assessment addresses cosmetic ingredients that are N-acyl derivatives of sarcosine and are generally referred to as acyl sarcosines, and those that are salts, known generally as acyl sarcosinates. Previous assessments have addressed the safety of each of the fatty acids that appear in these acyl sarcosines and sarcosinates (Coconut Acid, Oleic Acid, Lauric Acid, and Myristic Acid). In each case the fatty acid was either safe for use or safe as used in cosmetic formulations. Acyl sarcosines are considered modified fatty acids with greater solubility and increased acidity of the carboxylic acid group compared to the parent fatty acid. They are used in a large number of cosmetic formulations as hair-conditioning agents and surfactant-cleansing agents. In soaps, concentrations are reported to be as high as 12.9%. These ingredients have low oral toxicity in rats. Although cytotoxic to Chinese hamster cells in culture, acyl sarcosines and sarcosinates are not mutagenic in those cells, nor in bacterial cells in culture. Carcinogenicity data were not available. These ingredients are nonirritating and nonsensitizing to animal and human skin, although they can enhance the penetration of other ingredients through the skin. For that reason, caution should be exhibited in formulating cosmetic products that contain these ingredients in combination with other ingredients whose safety is based on their lack of absorption or where dermal absorption is a concern (e.g., HC Yellow No. 4, Disperse Yellow 3). Because sarcosine can be nitrosated to form N-nitrososarcosine, a known animal carcinogen, these ingredients should not be used in cosmetic products in which N-nitroso compounds may be formed. With the above caveat, and based on the available data, it was concluded that these acyl sarcosines and sarcosinates are safe as used in rinse-off products. They may be safely used in leave-on products at concentrations up to 5%, the highest concentration tested in clinical irritation and sensitization studies. Oleoyl Sarcosine is used as a corrosion inhibitor in some aerosol products, at extremely low concentrations. In this circumstance, the ingredient is not being used as a cosmetic ingredient and this report is not intended to limit that use. Because of the absence of data on inhalation toxicity, however, it was concluded that the available data were not sufficient to support the safety of acyl sarcosines and sarcosinates as cosmetic ingredients in products where they are likely to be inhaled.

Administration, Inhalation↗
PubMed1975

Drug induced biogenesis of nitrosamines.

It has been demonstrated that potentially corcinogenic nitroso compounds are readily formed when certain widely used drugs with secondary alkylaminostructures (e.g. nortriptyline and fenfluramine) or drug metabolities with such structures (e.g. norpropoxyphene) are reacted with nitrite in dilute acid aqueous medium or in human gastric juice under simulated gastric conditions. The reactions occur so readily in vitro that new quantitative procedures for the determination of these drugs have been developed and based on these principles. The potential hazards associated with the long term clinical use of such drugs are discussed.

Carcinogens↗
PubMed2002

Red meat intake, CYP2E1 genetic polymorphisms, and colorectal cancer risk.

N-Nitroso compounds are suspected colorectal cancer (CRC) carcinogens to which individuals on a diet high in red meat (RM) may be particularly exposed. Many of these compounds undergo alpha-hydroxylation by CYP2E1 to form DNA adducts. The gene coding for this enzyme is polymorphic and thus may constitute a susceptibility factor for CRC. We conducted a population-based case-control study in Hawaii to test the association of two functional polymorphisms in CYP2E1 (the G1259C RsaI substitution and a 5' 96-bp insertion variant) with CRC, as well as their modifying effects on the association of RM and processed meat (PM) with this cancer. We obtained interviews and blood samples for 521 patients with CRC (165 with rectal cancer) and 639 controls of Japanese, Caucasian, or Hawaiian origin. Genotyping was performed by PCR. After adjustment for CRC risk factors, subjects with the 5' insert variant were found to be at a 60% increased risk (95% confidence interval, 1.1-2.5) for rectal cancer. Subjects who carry the insert and who were predicted to have been exposed to increased levels of nitrosamines, based on their high intake of RM or PM, were at a markedly greater increased risk (2- and 3-fold for RM and PM, respectively) for rectal cancer. No clear association was found for colon cancer. A similar increase in rectal cancer risk was found for CYP2E1 insert carriers who consumed salted/dried fish or Oriental pickled vegetables. These data provide additional support for the hypothesis that nitrosamines are carcinogenic to the rectum in humans and that RM and, in particular, PMs are significant sources of exposure for these compounds.

Case-Control Studies↗