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PubMed1984

A transforming ras gene in tumorigenic guinea pig cell lines initiated by diverse chemical carcinogens.

Fetal guinea pig cells were transformed by treatment with four different chemical carcinogens including nitroso compounds and polycyclic hydrocarbons. As a consequence of this treatment, oncogenes capable of transforming NIH/3T3 cells became activated in each of five independently established clonal guinea pig cell lines. Molecular characterization of representative NIH/3T3 transformants revealed that the same oncogene was present in each of the cell lines tested. Moreover, detection of this transforming gene paralleled the acquisition of tumorigenic properties by these neoplastic cells.

Animals↗

PubMed1999

Relationship between schistosomiasis and bladder cancer.

Carcinoma of the urinary bladder is the most common malignancy in the Middle East and parts of Africa where schistosomiasis is a widespread problem. Much evidence supports the association between schistosomiasis and bladder cancer: this includes the geographical correlation between the two conditions, the distinctive patterns of gender and age at diagnosis, the clinicopathological identity of schistosome-associated bladder cancer, and extensive evidence in experimentally infected animals. Multiple factors have been suggested as causative agents in schistosome-associated bladder carcinogenesis. Of these, N-nitroso compounds appear to be of particular importance since they were found at high levels in the urine of patients with schistosomiasis-associated bladder cancer. Various strains of bacteria that can mediate nitrosation reactions leading to the formation of N-nitrosamines have been identified in the urine of subjects with schistosomiasis at higher intensities of infection than in normal subjects. In experimental schistosomiasis, the activities of carcinogen-metabolizing enzymes are increased soon after infection but are reduced again during the later chronic stages of the disease. Not only could this prolong the period of exposure to activated N-nitrosamines, but also inflammatory cells, stimulated as a result of the infection, may induce the endogenous synthesis of N-nitrosamines as well as generating oxygen radicals. Higher than normal levels of host cell DNA damage are therefore anticipated, and they have indeed been observed in the case of alkylation damage, together with an inefficiency in the capacity of relevant enzymes to repair this damaged DNA. In experimental schistosomiasis, it was also found that endogenous levels of host cell DNA damage were related to the intensity of infection. All of these factors could contribute to an increased risk of bladder cancer in patients with schistosomiasis, and in particular, the gene changes observed may have potential for use as biomarkers in the early detection of bladder cancer that may assist in alleviating the problem.

Animals↗

PubMed1985

Bacillus subtilis mutants deficient in the adaptive response to simple alkylating agents.

Three mutant strains exhibiting hyper-sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine, but not to methyl methanesulfonate, were selected by a replica method from mutagenized spores of Bacillus subtilis. All three were totally deficient in the adaptive response to N-methyl-N'-nitro-N-nitrosoguanidine with regard to both lethality and mutagenesis. The activity to destroy O6-methylguanine residues in the methylated DNA was not elevated in the mutant cells by the pretreatment with sublethal concentrations of N-methyl-N'-nitro-N-nitrosoguanidine. This deficiency corresponded to the persistence of O6-methylguanine residues in the DNA of both control and pretreated mutant cells challenged with the drug. The lethal and mutagenic sensitivity of the mutant strains were observed only for methyl- or ethyl-nitroso compounds that are thought to be active as inducers and are also active in O-alkylation. Except for the insensitivity to methyl methanesulfonate, the phenotypes of these mutants look very similar to those of ada mutants isolated previously in Escherichia coli.

Alkylating Agents↗

PubMed1978

Nitrite studies in oesophageal cancer.

As nitrate consumption may have considerable importance for the in vivo formation of nitrites and potentially carcinogenic N-Nitroso compounds, we have studied salivary nitrite levels in patients with oesophageal cancer and adult volunteers before and after administering 100 ml beet juice containing 160 mg nitrate. Initial salivary nitrite levels were slightly lower in the cancer patients, perhaps because of previous malnutrition. In both groups there was a marked increase in salivary nitrite levels 90 minutes after ingesting beet juice and the attained levels in the two groups were similar. The results imply that formation of salivary nitrite is highly dependent on exogenous dietary nitrate and that there is no difference in the capacity to form nitrites between oesophageal cancer patients and healthy adult subjects.

Adult↗

PubMed1996

Ascorbic acid and total vitamin C concentrations in plasma, gastric juice, and gastrointestinal mucosa: effects of gastritis and oral supplementation.

Epidemiological evidence suggests that high dietary ascorbic acid reduces gastric cancer risk. It may do this by either reducing N-nitroso compound formation in gastric juice, or by scavenging reactive oxygen species in gastric mucosa. The aim of this study was to discover if potential ascorbic acid protection might be increased by supplementation. Thirty two patients were supplemented with ascorbic acid, 500 mg twice daily for two weeks. Gastric juice, plasma, and upper gastrointestinal biopsy ascorbate concentrations were measured and compared with values in 48 unsupplemented patients. It was found that ascorbic acid and total vitamin C concentrations were considerably higher in biopsy specimens from oesophagus, body, antrum, duodenum, and rectum, compared with values in plasma or gastric juice. Plasma and mucosal concentrations were unaffected by the presence of chronic gastritis but gastric juice concentrations were substantially lower in patients with chronic gastritis than in patients with normal histological assessment (p < 0.01). Patients receiving ascorbic acid supplements had higher ascorbic acid concentrations in plasma (p < 0.001), gastric juice (p < 0.001), and at all biopsy sites in the upper gastrointestinal tract (p < 0.05). Gastric juice ascorbic acid and total vitamin C concentrations in gastritic patients, however, were still less after supplementation than in normal subjects (p < 0.01). These data suggest that high ascorbic acid intake could reduce gastric cancer risk, but its protective effect might be greater if gastritis is treated (for example, by Helicobacter pylori eradication).

Adult↗

PubMed2000

Elevated levels of the pro-carcinogenic adduct, O(6)-methylguanine, in normal DNA from the cancer prone regions of the large bowel.

BACKGROUND: The pro-mutagenic lesion O(6)-methyldeoxyguanosine (O(6)-MedG), a marker of exposure to many N-nitroso compounds (NOC), can be detected in normal and tumour DNA isolated from colorectal tissue. The biological significance of this exposure is, as yet, unknown but in situ NOC formation is bacterially catalysed suggesting that NOC formation and potentially DNA alkylation will vary throughout the large bowel. AIMS: To determine if O(6)-MedG levels in colorectal DNA vary within the large bowel. PATIENTS: We studied 62 men and women undergoing surgery for colorectal tumours in the north west of England. METHODS: O(6)-MedG levels were measured in paired normal and tumour DNA samples. DNA was digested to nucleosides, fractionated by HPLC, and purified O(6)-MedG quantified by a radioimmunoassay. RESULTS: O(6)-MedG was detected in 27 out of a total of 62 (43%) normal DNA samples and in 30 of 58 (52%) tumour DNA samples: it was present at concentrations of <0. 01-0.94 and <0.01-0.151 micromol O(6)-MedG/mol deoxyguanosine for normal and tumour DNA, respectively. Levels of O(6)-MedG in normal, but not tumour, DNA from the proximal colon were lower than those found in DNA from either the sigmoid colon (p=0.03) or rectum (p=0. 05). When the analysis was restricted to samples that contained O(6)-MedG, similar results were obtained in that O(6)-MedG levels in normal DNA were lower in the proximal colon than in the sigmoid colon (p=0.04) or rectum (p=0.03). CONCLUSIONS: DNA alkylation varied within the large bowel possibly due to in situ NOC formation and was highest in areas of the colon and rectum where the highest incidence of large bowel tumours occurs, suggesting that DNA alkylation may play a role in the aetiology of colorectal cancer.

Aged↗

PubMed2004

Agricultural pesticide use and adenocarcinomas of the stomach and oesophagus.

AIMS: To evaluate the risk of the stomach and oesophageal adenocarcinomas associated with farming and agricultural pesticide use. METHODS: Population based case-control study in eastern Nebraska. Telephone interviews were conducted with men and women diagnosed with adenocarcinoma of the stomach (n = 170) or oesophagus (n = 137) between 1988 and 1993, and controls (n = 502) randomly selected from the same geographical area. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs) for farming and for use of individual and chemical classes of insecticides and herbicides, including pesticides classified as nitrosatable (able to form N-nitroso compounds on reaction with nitrite). Non-farmers were used as the reference category for all analyses. RESULTS: Ever living or working on a farm, duration of farming, and size of the farm were not associated with stomach or oesophageal adenocarcinomas. There was no association for either cancer with ever-use of insecticides (stomach OR 0.9, 95% CI 0.6 to 1.4; oesophagus OR 0.7, 95% CI 0.4 to 1.1) or herbicides (stomach OR 0.9, 95% CI 0.5 to 1.4; oesophagus OR 0.7, 95% CI 0.4 to 1.2). Likewise, individual pesticides, including individual nitrosatable pesticides, were not significantly associated with risk. CONCLUSIONS: No significant associations were found between specific agricultural pesticide exposures and the risk of stomach or oesophageal adenocarcinomas among Nebraska farmers.

Adenocarcinoma↗

PubMed2003

Occupation and gastric cancer.

Gastric cancer is a cause of significant morbidity and mortality. There are several risk factors, with occupation emerging as one of these. There is considerable evidence that occupations in coal and tin mining, metal processing, particularly steel and iron, and rubber manufacturing industries lead to an increased risk of gastric cancer. Other "dusty" occupations-for example, wood processing, or work in high temperature environments have also been implicated but the evidence is not strong. The mechanism of pathogenesis of gastric cancer is unclear and the identification of causative agents can be difficult. Dust is thought to be a contributor to the pathological process, but well known carcinogens such as N-nitroso compounds have been detected in some environments. Further research on responsible agents is necessary and screening for detection of precursor gastric cancer lesions at the workplace merits consideration.

Chemical Industry↗

PubMed1991

N omega-nitro-L-arginine selectively inhibits vasodilator responses to acetylcholine and bradykinin in cats.

The effects of N omega-nitro-L-arginine (nitroarginine), an inhibitor of endothelium-dependent relaxing factor (EDRF) production, on vascular tone and responses to vasodilator and vasoconstrictor agents were investigated in the hindquarters vascular bed of the cat. Under constant flow conditions, infusion of nitroarginine into the hindquarters vascular bed caused a significant increase in systemic arterial and hindquarters perfusion pressures. During infusion of nitroarginine, hindquarters vasodilator responses to acetylcholine and bradykinin were reduced significantly whereas vasodilator responses to isoproterenol, PGE1, nitroprusside, and 8-bromoguanosine 3',5'-cyclic monophosphate were not altered. Infusion of nitroarginine significantly enhanced vasoconstrictor responses to the thromboxane receptor agonist U 46619 and to phenylephrine. The results of these studies are consistent with the hypotheses that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine, and that EDRF production may play a role in the regulation of vascular tone and in the mediation of responses to the endothelium-dependent vasodilators, acetylcholine and bradykinin, in resistance vessels in the hindquarters. These data support the concept that EDRF is very likely an endogenous nitrovasodilator derived from L-arginine in the hindquarters vascular bed of the cat.

Acetylcholine↗

PubMed1991

LTD4 and bradykinin evoke endothelium-dependent relaxation of the renal vein: dissimilar mechanisms.

This study's goals were to define the vasomotor effects of the peptide leukotriene (LT)D4 on norepinephrine (NE)-contracted isolated rings of canine renal vein (RV) and to compare these influences with those of bradykinin (BK). Canine RV rings were connected to isometric force transducers and bathed in Krebs-Ringer bicarbonate buffer containing indomethacin (10-5M). LTD4 and BK evoked dose-dependent decreases in tone of NE-contracted RV rings that were abolished by physical removal of the endothelium. Relaxation of the RV ring produced by glyceryl trinitrate (GTN) was slightly enhanced or unaltered after endothelium denudation. Reduced human hemoglobin (Hb, 10(-6) M), NG-monomethyl-L-arginine (L-NMMA, 300 microM) and methylene blue (MB, 10(-6) M) had no effect on LTD4-induced venomotor relaxation, whereas they significantly decreased the vasorelaxant effect of BK. In contrast, endothelium-dependent relaxation of renal arterial rings produced in response to both LTD4 and BK was markedly attenuated in the presence of either reduced Hb (10(-6)M) or MB (10(-6) M). MB significantly attenuated venorelaxant responses to GTN (10(-8) to 10(-6) M). The ATP-sensitive K(+)-channel blocker glybenclamide (10(-6)M) inhibited relaxation of the RV induced by cromakalim (5 x 10(-8)M) but had no effect on LTD4-evoked relaxation. These data indicate that endothelium-dependent relaxation of the RV elicited by BK is dependent on "classic" endothelium-derived relaxing factor (EDRF) considered to be nitric oxide (NO) or an unstable nitroso compound that ultimately liberates the NO radical.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

EDRF and nitric oxide production in cultured endothelial cells: direct inhibition by E. coli endotoxin.

Recent studies have yielded contradictory interpretations about the influence of gram-negative endotoxin on endothelium-derived relaxing factor (EDRF). We tested the hypothesis that Escherichia coli endotoxin exerts primary facilitatory or, alternatively, inhibitory actions on EDRF release and the synthesis of either nitric oxide or a nitroso compound in cultured endothelial cells. Bovine aortic endothelial cells were grown on microcarrier beads and either exposed acutely (30 min) to E. coli endotoxin or incubated with endotoxin for 1 h followed by a 1-h wash (prolonged exposure). EDRF bioactivity was measured under basal, bradykinin-stimulated, and A23187-stimulated conditions using standard isometric tension recordings. EDRF-derived nitric oxide was quantitated using a specific chemiluminescence technique. Endotoxin (0.005-5 micrograms/ml) decreased EDRF bioactivity and nitric oxide production under both basal and bradykinin-stimulated conditions after prolonged, but not acute, exposure. A23187-stimulated EDRF bioactivity and nitric oxide production were minimally, albeit significantly, reduced after endotoxin. The present results demonstrate that EDRF activity and nitric oxide production are decreased in vascular endothelial cells exposed to endotoxin. Endotoxin itself failed to directly stimulate EDRF release from endothelium. Alternative sources of nitrovasodilators, endothelium-independent effects, or release of other vasoactive mediators by endotoxin may be responsible for systemic hypotension during in vivo endotoxemia.

Animals↗

PubMed1996

Nitric oxide and nitroglycerin reversal of pulmonary vasoconstriction induced by alpha-activation during exercise.

We have previously shown in sheep that pulmonary vascular resistance decreases rapidly after the onset of constant exercise, followed by a slower and smaller second vasodilation. The second phase is partly regulated by alpha- and beta-adrenoceptor activation. We examined the effect of inhaled nitric oxide (NO; 40 ppm) and intravenous nitroglycerin on beta-adrenergic blockade-induced pulmonary vasoconstriction during exercise. In paired studies, we exercised eight sheep at a constant rate of 4 miles per hour for 4 min on a treadmill and measured the hemodynamic response during beta-blockade (propranolol, 1 mg i.v.) with and without 40 ppm inhaled NO or continuous infusion of nitroglycerin (3.2-4.0 micrograms.kg-1.min-1). beta-Blockade resulted in a higher pulmonary vascular resistance during steady-state exercise (40-240 s) than in the unblocked state; reduction in pulmonary vascular resistance during the second phase of exercise was smaller with beta-blockade (13-16%) than with control exercise (26-30%). Inhaled NO and nitroglycerin reversed the beta-blockade-related pulmonary vasoconstriction to the levels of control exercise. Inhaled NO and intravenous nitroglycerin also reversed the pulmonary vasoconstriction produced by intravenous phenylephrine at rest. We conclude that exogenous NO, delivered by gas inhalation or via nitroso compounds, opposes and fully reverses alpha-receptor-activated pulmonary vasoconstriction during exercise in sheep.

Administration, Inhalation↗

PubMed1991

N omega-nitro-L-arginine methyl ester selectively inhibits pulmonary vasodilator responses to acetylcholine and bradykinin.

The effects of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor (EDRF) production, on vascular tone and responses were investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was elevated with U-46619, intralobar injections of acetylcholine, bradykinin, sodium nitroprusside, isoproterenol, prostaglandin E1 (PGE1), lemakalim, and 8-bromo-guanosine 3',5'-cyclic monophosphate (8-bromo-cGMP) dilated the pulmonary vascular bed. Intravenous administration of L-NAME elevated lobar arterial and systemic arterial pressures without altering left atrial pressure. When U-46619 was infused after L-NAME to raise lobar arterial pressure to levels similar to those attained during the control period, vasodilator responses to acetylcholine and bradykinin were reduced significantly, whereas responses to PGE1, lemakalim, and 8-bromo-cGMP were not altered, and responses to nitroprusside were increased. There was a small effect on the response to the highest dose of isoproterenol, and pressor responses to BAY K 8644 and angiotensin II were not altered. These results are consistent with the hypothesis that EDRF production may involve the formation of nitric oxide or a nitroso compound from L-arginine and that EDRF production may have a role in the regulation of tone and in the mediation of responses to acetylcholine and bradykinin in the pulmonary vascular bed of the cat.

Acetylcholine↗

PubMed2006

Bladder tumor contains higher N7-methylguanine levels in DNA than adjacent normal bladder epithelium.

Schistosoma haematobium-infected patients are more likely to develop bladder cancer and be more exposed to carcinogenic N-nitroso compounds than uninfected patients. As N7-methylguanine is a marker of exposure to methylating agents of this type, we have measured N7-methyldeoxyguanosine 3'-monophosphate (N7-MedGp) by (32)P postlabeling. DNA was isolated from 42 paired normal and tumor tissue of Egyptians with bladder cancer. N7-MedGp was detected in DNA from 93% of the tumors and 74% of the normal bladder tissue samples. Adduct levels were highly variable and ranged from 0.04 to 6.4 and from 0.02 to 0.72 micromol/mol deoxyguanosine 3'-monophosphate (dGp) in tumor and normal DNA, respectively. N7-MedGp levels in normal and tumor DNA were highly correlated with one another (P = 0.007). The mean difference (95% confidence interval) in adduct levels between tumor and normal DNA was 0.21 (0.13-0.32) micromol/mol dGp and this was statistically significant (P < 0.001). The adduct ratio (tumor DNA/normal DNA) varied between 0.2 and 136 (median, 4.6). N7-MedGp levels were not associated with gender, age, or the presence of schistosomiasis. However, lower N7-MedGp levels were found in normal DNA from individuals lacking the GSTM1 gene (P = 0.03) but not the GSTT1 gene or in subjects with the Ile105Val GSTP1 polymorphism. These results show that exposure to methylating agents is widespread and suggest that such exposure may play a role both in tumor initiation and progression.

Bacterial Infections↗

PubMed1980

The exposure to humans to nitrite.

Although nitrate is more abundant than nitrite in food and the environment in general, it requires reduction by, for instance, bacterial or plant enzymes before it is involved in the nitrosation of amines or amides. Part of the exposure of humans to nitrite arises from its use as a food additive where it performs a very useful function in protecting the consumer from pathogenic micro-organisms such as Clostridium botulinum. Some untreated foodstuffs, such as potatoes, tomatoes and beets, also contain low levels of nitrite. Nevertheless, the main source of human contact is that produced in vivo from nitrate ingested in foods in general and in vegetables in particular. Nitrate also occurs widely in drinking water supplies and this source can also contribute in some measure to human exposure. As yet, it is not possible to compute with accuracy the contribution from any endogenous synthesis within the gastrointestinal tract. Since the rate of nitrosation of an amine is dependent on the nitrite concentration to a power of greater than unity, it is probable that nitrite ingested in one application over a short period will be more active in the synthesis of N-nitroso compounds than a continuous supply at lower concentrations over long periods.

Drinking↗

PubMed1991

Release of nitrogen oxides from cultured bovine aortic endothelial cells is not impaired by calcium channel antagonists.

BACKGROUND: The endothelium-derived relaxing factor has been shown to be nitric oxide or a related nitroso compound, synthesized by the enzyme nitric oxide synthetase, which oxidizes the guanidono nitrogens of arginine. This enzyme is activated by increases in cytosolic calcium. The effect of the clinically used calcium channel antagonists on this process is controversial. The present study was performed to determine whether calcium channel blockade with these pharmacologic agents would alter the activity of nitric acid synthetase in intact endothelial cells. METHODS AND RESULTS: A specific and sensitive chemiluminescence assay was used to measure the release of nitrogen oxides (nitric oxide and one-electron oxidation products of nitric oxide) from bovine aortic endothelial cells grown in culture. Under basal conditions, the release of nitrogen oxides was about 0.2 nmol/100 micrograms protein/hr. Bradykinin doubled this response. Removal of extracellular calcium abolished basal and bradykinin-stimulated release of nitrogen oxides. Neither diltiazem, verapamil, nor nifedipine in concentrations that are encountered clinically altered the release of nitrogen oxides. CONCLUSIONS: These experiments show that although the production of nitrogen oxides is dependent on extracellular calcium, the clinically used calcium channel antagonists do not inhibit the release of the endothelium-derived relaxing factor.

Amino Acid Oxidoreductases↗

PubMed1992

Pulmonary vasodilator response to vagal stimulation is blocked by N omega-nitro-L-arginine methyl ester in the cat.

The effect of N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of endothelium-derived relaxing factor production, on the vasodilator response to efferent vagal stimulation was investigated in the pulmonary vascular bed of the intact-chest cat under conditions of controlled blood flow and constant left atrial pressure. When pulmonary vascular tone was increased with U46619, efferent vagal stimulation decreased lobar arterial pressure in a stimulus-frequency-dependent manner. The decreases in lobar arterial pressure were enhanced by pretreatment with reserpine, were blocked by atropine, and were not altered by propranolol, indicating that the neurogenic vasodilator response was cholinergic in nature. The decreases in lobar arterial pressure in response to vagal stimulation and to exogenously administered acetylcholine were reduced after administration of L-NAME (100 mg/kg i.v.). Although L-NAME decreased pulmonary vasodilator responses to vagal stimulation and to acetylcholine, responses to adenosine, nicorandil, lemakalim, isoproterenol, prostaglandin E1, sodium nitroprusside, and 8-bromo-cGMP, agents that act by a variety of mechanisms, were not decreased. These results are consistent with the hypothesis that efferent vagal stimulation releases acetylcholine, which dilates the pulmonary vascular bed by stimulating the production of nitric oxide or a labile nitroso compound from L-arginine.

Animals↗

PubMed1986

Comparison of the acute toxicity of N-nitrosocimetidine with three structurally related carcinogens in the rat.

The acute toxicity of N-nitrosocimetidine, the nitrosated derivative of the histamine H2-receptor blocking agent cimetidine, was compared with the toxicities of three structurally related nitroso compounds known to be potent carcinogens, namely N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, and N-methyl-N-nitrosourethane, and also with the parent drug cimetidine. The acute toxicity of each compound was investigated in 6-week-old female Fischer-344 rats by estimating the median lethal doses via three different routes of administration, and by assessing the sequence of histopathological alterations induced. According to median lethalities, all three known carcinogens were substantially more toxic than nitrosocimetidine whether administered by the intravenous, intraperitoneal, or oral routes. The widest margin of difference was represented by orally administered N-methyl-N-nitrosourea, the median lethal dose being 59 times greater than oral N-nitrosocimetidine. By this method, the acute toxicities of N-nitrosocimetidine and the parent drug cimetidine were virtually identical for each of the three routes of administration. Sequential histological assessment indicated that the three known carcinogens induced specific pathological alterations mainly in organs which were also known to be targets for their carcinogenic activity. In contrast, no tissue lesions of a specific nature were associated with N-nitrosocimetidine or cimetidine in this study. The comparable results with N-nitrosocimetidine and the parent drug provide biological support for previously obtained biochemical data which suggested that N-nitrosocimetidine is rapidly denitrosated to cimetidine in the rat.

Administration, Oral↗