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PubMed2004

Pancreatic cancer and drinking water and dietary sources of nitrate and nitrite.

N-Nitroso compounds, known animal carcinogens, are formed endogenously from drinking water and dietary sources of nitrate and nitrite. The authors conducted a population-based case-control study of pancreatic cancer in Iowa to determine whether increased consumption of nitrate and nitrite from drinking water and dietary sources was associated with risk. They linked detailed water source histories to nitrate measurements for Iowa community water supplies. After exclusions for insufficient data, 1,244 controls and 189 pancreatic cancer cases were available for analysis. Among controls, the median average nitrate level (1960-1987) was 1.27 (interquartile range, 0.6-2.8) mg of nitrate nitrogen per liter of water. No association was observed between pancreatic cancer risk and increasing quartiles of the community water supplies' nitrate level. Increasing intake of dietary nitrite from animal sources was associated with an elevated risk of pancreatic cancer among men and women (highest quartile odds ratios = 2.3, 95% confidence interval: 1.1, 5.1, for men and 3.2, 95% confidence interval: 1.6, 6.4, for women). In contrast, dietary nitrate intake showed an inverse association with risk among women and no association among men. This study suggests that long-term exposure to drinking water nitrate at levels below the maximum contaminant level of nitrate nitrogen (10 mg/liter) is not associated with pancreatic cancer; however, the consumption of dietary nitrite from animal products may increase risk.

Adult↗
PubMed1997

Extra-pulmonary effects of inhaled nitric oxide in swine with and without phenylephrine.

We have compared the effects of inhaled nitric oxide (iNO) and i.v. nitroglycerin (ivGTN) on the haemodynamic response to phenylephrine-induced hypertension (PEHT) in anaesthetized pigs. PEHT did not change either pulmonary vascular resistance or gas exchange throughout all experiments. Both treatments lowered pulmonary arterial pressure to the same extent (-12.4% iNO; -13.7% ivGTN) and passively via an effect on left atrial pressure (-26.3% iNO; -31.4% ivGTN). Both treatments failed to reverse the decrease in renal blood flow (RBFc) induced by PEHT, but both increased urinary flow (UF) (+128% iNO; +148% ivGTN). IvGTN significantly increased plasma concentrations of nitrite and nitrate during (+22.7% arterial blood; +26.2% venous blood) and beyond the period of infusion (iNO: +6.4% and +4.9%, respectively). In four control pigs (no PEHT), iNO markedly increased RBFc (+109%), glomerular filtration rate (+72.5%) and UF (+68.7%). We conclude that iNO may have direct cardiac and renal effects, probably via intervention of NO carrier forms such as S-nitroso compounds.

Administration, Inhalation↗
PubMed1989

The effect of different sources of nitrate exposure on urinary nitrate recovery in humans and its relevance to the methods of estimating nitrate exposure in epidemiological studies.

It was demonstrated that nitrate concentration fluctuates dramatically in both urine and saliva throughout the study period and hence single time point ('spot') samples of either fluid give a poor measure of previous nitrate exposure. In contrast, the nitrate recovery in complete 24 h urine collections showed a strong positive correlation with previous nitrate exposure which was independent of the nature of the food matrix in which the nitrate was ingested. Regression analysis of the data showed that the apparent urinary recovery of 70% appears to consist of 55% arising from the original challenge and a background of approximately 0.22 mmol/day which is independent of the challenge and which may reflect endogenous mammalian synthesis of nitrate. It is therefore important that in future epidemiological studies, in which dietary nitrate exposures are to be determined, that analyses are conducted only on 24 h urine collections. A large inter-individual variation was found in the conversion of salivary nitrate to nitrite presumably mediated by the oral flora. The resulting differences in nitrite formation may be one of the factors determining the level of endogenous N-nitroso compound formation in an individual.

Diet↗
PubMed1990

DNA methyl-adduct dosimetry and O6-alkylguanine-DNA alkyl transferase activity determinations in rat mammary carcinogenesis by procarbazine and N-methylnitrosourea.

The metabolism of the carcinogenic antitumor drug procarbazine (PCZ) is complex with the ultimate production, among other metabolites, of a methyldiazonium ion which is also the ultimate carcinogenic species of the DNA-methylating N-nitroso compounds including N-methylnitrosourea (MNU). This suggests a similar mechanism of carcinogenic action. Following a single oral dose of [14C]PCZ (50 mg/rat) to 50 day old female Sprague-Dawley rats under the reported conditions of mammary gland carcinogenicity, the DNA adducts 7-methylguanine (7-meG) and O6-methylguanine (O6-meG) were determined in target (mammary gland) and non-target organs. The degree of DNA methylation was similar in all the organs considered. In the mammary gland, lung, spleen, small intestine and stomach the O6-meG/7-meG ratio was close to 0.11. At a lower dose of PCZ (26 mg/rat), the levels of 7-meG in the tissues were 40-60% of those produced by the higher dose. Eighty percent of the rats given the higher dose versus 37% of those given the lower dose developed mammary tumors after 20 weeks. With the higher dose of MNU (50 mg/kg body wt) DNA methylation was more or less uniform in all the organs including the mammary gland, with slightly greater yields in the liver. At a lower MNU dose (25 mg/kg) the levels of 7-meG were 40-48% of those produced by the higher dose. Fifty seven percent of the rats given the higher dose versus 21% of the animals given the lower dose developed mammary gland tumors after 20 weeks. On a mol/kg body wt basis, PCZ was approximately 5-times less active than MNU in the production of 7-meG in mammary gland but only approximately 2-times less active than MNU in the production of mammary gland tumors. The O6-alkylguanine-DNA alkyltransferase (AGT) levels in the liver, kidney, spleen and lung of PCZ or MNU treated rats were approximately 9-28% (expressed relative to protein content) and 10-33% (expressed relative to homogenate DNA content) of those in the corresponding organs of the saline-treated controls. However, the AGT levels of the mammary gland and brain were in the range of 45-61% (expressed relative to protein content) and 39-54% (expressed relative to homogenate DNA content) of those of the saline-treated controls. Also the mammary gland of the 50 day old female rats has the lowest AGT activity (expressed relative to DNA content).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Increased urinary nitrosamine excretion in paraplegic patients.

An increased risk of bladder cancer is a recognized complication in spine-injured patients undergoing long-term urethral catheterization to preserve renal function. Aerobic cultures from 28 of 30 paraplegic patients showed complex bacterial flora containing nitrate-reducing organisms (Escherichia coli, Proteus and Klebsiella spp.). Urine samples from 29 paraplegic patients were also found to contain volatile nitrosamines. Mean N-nitrosamine excretion levels were 0.65 +/- 0.69 micrograms/day N-nitrosodimethylamine, 0.25 +/- 0.44 micrograms/day N-nitrosopiperidine and 0.39 +/- 0.50 micrograms/day N-nitrosopyrrolidine. A mean urinary nitrite excretion of 10.4 +/- 13.2 mg/day was found in 24 out of 30 paraplegic patients. In the sterile urine of control volunteers (medical staff attending the paraplegic patients and in-patients from other wards of the hospital), no urinary excretion of volatile N-nitrosamines and nitrite was found. The results clearly demonstrate a bacterially mediated in vivo formation of N-nitroso compounds in the urinary tracts of paraplegic patients which may be an important etiological risk factor for bladder cancer in this patient group.

Amines↗
PubMed1991

Evaluation of the newborn mouse model for chemical tumorigenesis.

A total of 45 chemicals, including two aromatic hydrocarbons, five aromatic amines, three azo dyes, ten nitroso compounds, three steroids, four tryptophan metabolites and their related compounds, four naturally occurring substances, four pyrolysates of amino acids and ten miscellaneous compounds, were tested for newborn mouse tumorigenesis assay (NMTA). The results of the NMTA were compared with data from 'Survey of Compounds Which Have Been Tested for Carcinogenic Activity', NIH, NCI, USA (SCWHBTCA), and also with data from the IARC Monographs (Vols 1-41), Lyon, France (IARC). Of the 45 chemicals tested by the NMTA, 28 chemicals showed positive results in the NMTA, and the remaining 17 chemicals were found to be negative for tumor development. The correlation of the results between the NMTA and the mouse and/or rat carcinogenesis test starting at young adult age reported in the SCWHBTCA and in the IARC were compared with 37 chemicals tested; the remaining eight chemicals were found only in our NMTA results. It can be concluded that 31 out of 37 chemicals (83.8%) tested by the NMTA showed similar carcinogenic or non-carcinogenic results obtained in either adult mouse and/or rat carcinogenesis tests. The remaining six chemicals showed contradictory results between the NMTA and either adult mouse and/or rat carcinogenesis tests. Those six chemicals were N-hydroxy-4-acetylaminobiphenyl, estradiol, 3-hydroxyanthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. Among the 37 chemicals, 34 were comparable with the results of the adult mouse carcinogenesis test and those of the NMTA. Twenty-nine out of 34 chemicals (85.3%) showed similar results to the adult mouse carcinogenesis test. Contradictory results were obtained with the following five chemicals: N-hydroxy-acetylaminobiphenyl, 3-hydroxy-anthranilic acid, 3-hydroxy-L-kynurenine, isonicotinic acid hydrazide and phenobarbital. There were 35 chemicals which were comparable with the results of the adult rat carcinogenesis test, and 32 chemicals showed the same results as the NMTA (91.4%). Dissimilar results were obtained with the following three chemicals: estradiol, 3-hydroxy-anthranilic acid and phenobarbital. Based on the results presented in this report, it is reasonable to conclude that the NMTA is one of the most useful and reliable methods for detecting tumorigenic or non-tumorigenic chemicals, when a small amount of chemical is available for rodent carcinogenesis test and the duration of the study is limited to 1 year.

Animals↗
PubMed1992

Chemical carcinogens and overnutrition in diet-related cancer.

The intake of known dietary carcinogens was compiled and the cancer risk was estimated on the basis of carcinogenic potencies in animals as derived from the Carcinogenic Potency Database by Gold and co-workers. The total cancer risk was compared with the number of cancer cases attributed by epidemiologists to dietary factors (one-third of all cancer cases, i.e. approximately 80,000 per one million lives). Except for alcohol, the known dietary carcinogens could not account for more than a few hundred cancer cases. This was seen both with the DNA-reactive carcinogens (heterocyclic aromatic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, estragole, aflatoxin B1, ethyl carbamate, to name the most important factors) as well as with those carcinogens which have not been shown to react with DNA (e.g. caffeic acid and the carcinogenic metals arsenic and cadmium). Residues and contaminants turned out to be negligible. Among the various possibilities to explain the discrepancy we investigated the role of overnutrition. Dietary restriction in animals is well known for its strong reducing effect on spontaneous tumor formation. These data can be used to derive a carcinogenic potency for excess macronutrients: the tumor incidence seen with the restricted animals is taken as a control value and the increased tumor incidence in the animals fed ad libitum is attributed to the additional feed intake. For excess standard diet in rats, a carcinogenic potency TD50 of 16 g/kg/day was deduced from a recent study. Overnutrition in Switzerland, estimated to be 5.5 kcal/kg/day, was converted to excess food (1.9 g/kg/day) and the cancer incidence was calculated. The result, 60,000 cancer cases per one million lives, is provocatively close to the number of cases not explained by the known dietary chemical carcinogens. Mechanistic studies will be required to test our hypothesis and investigate the role of different types of macronutrients in overnutrition.

Carcinogens↗
PubMed1993

7-Alkyldeoxyguanosine adduct detection by two-step HPLC and the 32P-postlabeling assay.

7-Alkyldeoxyguanosine DNA adducts may be a marker for some N-nitroso compound exposures and subsequent human cancer risk. A sensitive and highly specific assay for the detection of 7-methyl-2'-deoxyguanosine-3'-monophosphate (7-methyldGp) and 7-ethyl-2'-deoxyguanosine-3'-monophosphate (7-ethyldGp) has been developed by combining two different HPLC purification steps with the 32P-postlabeling assay. We previously reported that ion-pair reverse-phase (IP) chromatography coupled with the 32P-postlabeling assay detects 7-methyldGp in human lung, but have found that other nucleotides and unknown adducts co-elute. Thus, weak anion exchange (AE) HPLC was added in tandem with IP HPLC prior to the 32P-postlabeling assay. 2'-Deoxyguanosine-3'-monophosphate (dGp) is incorporated into the assay as an internal standard for the assessment of enzyme labeling efficiency and adduct recovery. The methodology was validated using radiolabeled DNA and liquid scintillation counting, which accounts for adduct loss from enzymatic digestion to detection. Levels of 7-ethyldGp also were correlated with accelerator mass spectrometry. The overall adduct recovery with this method was 58% for 7-methyldGp and 98% for 7-ethyldGp. The detection limit for both assays using 100 micrograms of DNA was one adduct in 10(8) unmodified dGp. 7-MethyldGp and 7-ethyldGp levels were determined in ten human lung samples at levels of 1.4-5.4 and 0.6-3.1 adducts per 10(7) dGp respectively, and in five human lymphocyte samples at levels of 5.0-8.3 and 0.3-1.4 adducts per 10(7) dGp respectively. Combining the two HPLC purification steps and the 32P-postlabeling assay attains chemical specificity, retains sufficient quantitative sensitivity and should be useful in human biomonitoring studies.

Animals↗
PubMed1993

Promutagenic methylation damage in liver DNA of mice infected with Schistosoma mansoni.

Male and female BK-TO mice were infected with different numbers of Schistosoma mansoni cercariae under standard environmental conditions. Promutagenic methylation damage (O6-methyldeoxyguanosine; O6-MedG) was detected in liver DNA, but not in kidney, spleen or bladder DNA of infected animals. It was shown that levels of hepatic O6-MedG increased with increasing intensities of schistosomal infection. Possible mechanisms of action are discussed. These include the activating effects of schistosomes and their products on murine macrophages and subsequent endogenous formation of N-nitroso compounds by the activated macrophages.

Animals↗
PubMed1993

Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes.

Woodchuck (Marmota monax) hepatic cells, which were immortalized by the simian virus 40 large T antigen (SV40 Tag) produced nitric oxide (NO; measured as nitrite) in vitro from L-arginine (L-Arg) after lipopolysaccharide (LPS) treatment. NO synthesis was related to L-Arg and LPS concentration and plateaued at 1.0 mM L-Arg and 1.0 microgram/ml LPS. LPS-stimulated cells nitrosated morpholine to form N-nitrosomorpholine (NMOR) in the presence of L-Arg at pH 7.4. NMOR production increased 7-fold in LPS stimulated cells compared to unstimulated hepatocytes. N-nitrosodimethylamine (NDMA) was detected in the cell culture medium in the presence of LPS and L-Arg but without added dimethylamine. NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthase, inhibited formation of NO and NMOR, indicating that NO and nitrosating agents were formed via the L-Arg-nitric oxide pathway. These data are the first to report NO and N-nitrosamine production by immortalized hepatocytes and confirm earlier work showing that primary hepatocytes form NO in culture. This suggests that hepatic formation of N-nitroso compounds and/or NO could be an etiologic factor in hepatocellular carcinoma. Immortalized woodchuck hepatic cells may be useful as in vitro models to study the L-Arg-nitric oxide pathway and its possible role in liver carcinogenesis.

Animals↗
PubMed1994

Woodchuck hepatitis virus surface antigen induces nitric oxide synthesis in hepatocytes: possible role in hepatocarcinogenesis.

Woodchuck hepatitis virus surface antigen (WHsAg) stimulated hepatocytes in culture to produce nitric oxide (NO.), as evidenced by the accumulation of nitrite in the medium. NO. synthesis by hepatocytes was positively correlated with WHsAg concentration. WHsAg-induced NO. synthesis was inhibited by NG-monomethyl-L-arginine and anti-WHsAg antibody. To our knowledge, this is the first demonstration of an increase in NO. formation by a viral antigen. These data, when considered in the light of the known genotoxicity of NO., raise the possibility that viral hepatitis increases the risk of liver cancer by increasing the production of NO.. Long-term elevated production of NO. free radicals due to stimulation by WHsAg in chronic hepatitis may directly cause reactions with cellular DNA leading to mutagenesis, as well as the formation of hepatocarcinogenic N-nitroso compounds. This provides a new mechanism by which hepatitis B virus infection might hypothetically increase the risk of liver cancer.

Animals↗
PubMed1994

DNA adduct formation and assessment of aberrant crypt foci in vivo in the rat colon mucosa after treatment with N-methyl-N-nitrosourea.

N-Nitroso-compound DNA adduct formation in vivo and occurrence of aberrant crypt foci (ACF) were studied in the rat colon mucosa after a single, local treatment with a carcinogen, N-methyl-N-nitrosourea (MNU), using a simple surgical approach. A segment of F344 rat colon was ligated to make a pouch and injected with MNU solution. For the study of DNA adduct formation, the solution contained 50 microCi of [3H]MNU. The results demonstrated that similar ranges of carcinogen dose, i.e. 0.15 x 10(-2) - 1.5 x 10(-2) M MNU, could induce both DNA adduct formation and appearance of ACF in the rat colon with both parameters showing a nearly linear dose dependence. HPLC analysis revealed the DNA adducts to include both 7-methylguanine (7-mGua) and O6-methylguanine (O6-mGua) with the 7-mGua/O6-mGua ratio being 8.2-11.3:1 in the system used. Assessment of ACF development from 4 to 16 weeks after MNU treatment at a dose of 7.5 x 10(-2) M showed the numbers to increase up to the 8th week, followed by a decrease at weeks 12 and 16, when 40% of the ACF counted at the peak time point were still present. The percentage of large ACF (> or = 4 crypts/ACF) significantly increased with time. These results indicate a clear relation between DNA adducts and preneoplastic lesions, i.e. ACF. In conclusion, DNA adduct formation and ACF can be efficiently and simply detected in vivo by using the method described in the present paper.

Animals↗
PubMed1994

Flexibility and curvature of DNA duplexes containing O4-methylthymine: implications for DNA repair.

Nitroso compounds are known to induce mutations and cancer. We study the effect of one of their products, O4-methylthymine, on the structure and flexibility of DNA sequences. In particular, we focus on aspects of DNA that are relevant for the interaction with the repair protein, O6-alkylguanine-DNA alkyltransferase. In general, sequences that contain O4-methylthymine have greater local curvatures. Sequences in which O4-methylthymine is paired with adenine have larger regions of increased flexibility, a consistent bend in the direction of the major groove and strong oscillations in the major groove widths. On the other hand, sequences in which O4-methylthymine is paired with guanine have only sites of increased flexibility, short regions bent towards the major groove alternating with sites bent toward the minor groove and larger major groove widths than those of canonical B-DNA. These features may possibly lead to the difference in the efficiency with which repair proteins correct the lesions in the two base pairs. Further experimental data are needed to make more definitive conclusions.

Alkylation↗
PubMed1995

Metastasizing tumors in rats treated with alkylating carcinogens.

Tumors induced in approximately 2000 F344 rats by a number of carcinogenic N-nitroso compounds have been examined for their propensity to metastasize. The objective was to discover relations between the structure of the carcinogen, the tumor induced and the proportion of tumors that formed metastases. Treatments consisted of multiple doses of one of 16 nitrosamines or 19 alkylnitrosoureas, which were administered in drinking water, by gavage or by the intravesicular route. Male and female rats were included. Most of the carcinogens were mutagens in bacteria, but some were not; this had no bearing on the tendency of induced tumors to metastasize, nor did the extent of alkylation of DNA produced in vivo. Fewer malignant tumors appeared in the rats treated with nitrosamines than with alkylnitrosoureas, but more than twice as many of the former metastasized; many were carcinomas or hemangiosarcomas of the liver, of which very few were induced by alkylnitrosoureas. Tumors of the liver, lung, mammary gland and forestomach metastasized most commonly, whereas those of the esophagus, nasal mucosa, Zymbal gland, kidney mesenchyme, thyroid, urinary bladder and mesotheliomas seldom formed metastases; none of the tumors of the brain or intestines metastasized; no differences between males and females were noted. Some rare tumors, osteosarcomas and thymus lymphomas, metastasized frequently. The lungs and lymph nodes were the most common sites for metastases, but less frequently liver, heart, kidney, adrenal gland, omentum, peritoneum, esophagus and pancreas were involved. Higher doses were associated with greater numbers of metastasizing tumors among mutagenic or non-mutagenic carcinogens, as has been reported elsewhere. It appears that directly alkylating alkylnitrosoureas are no more likely (and probably less likely) to induce tumors with metastatic properties than are nitrosamines that require metabolic activation to form reactive proximate carcinogens.

Alkylating Agents↗
PubMed1995

Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours.

Much of bladder cancer in East Africa and the Middle East is attributed to chronic urinary infection with Schistosoma haematobium ('schistosomiasis'). Most schistosomal bladder cancer (SBC) is squamous cell carcinoma (SCC) and occurs in the fifth decade of life. In contrast, nonschistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcinoma (TCC). To shed light on the mechanisms underlying these different patterns of bladder cancer we looked for mutations in the p53 gene in SBC from 92 patients in Egypt, where schistosomiasis is hyperendemic. Patients' mean age at presentation of bladder cancer was 49.4 +/- 9.9 years and 90% had a clinical history of schistosomiasis and/or histological evidence of schistosomal eggs adjacent to the carcinoma. There were 53 SCC, 23 TCC, 13 adenocarcinomas and three other carcinomas. Thirty patients had tumours with mutations in exons 5-8 of the p53 gene: 17/53 SCC, 8/23 TCC, 4/13 adenocarcinomas and 1/3 other tumours. Of 19 mutations in SCC, 16 were base pair substitutions (BPS), two were deletions and one an insertion. Two tumours each contained two mutations. Of the BPS, nine were transitions at CpG dinucleotides and two were G-->T transversions. All the mutations in TCC were BPS: four were transitions at CpG dinucleotides and three were G-->C transversions. One TCC had two mutations. Of four adenocarcinomas with mutations, two had transitions at CpG dinucleotides. Of the 30 BPS mutations, 16 were transitions at CpG dinucleotides, of which 12 were C-->T. We combined these 33 mutations with six obtained from Egyptian SCC reported by Habuchi et al. (Cancer Res., 53, 3795-3799, 1993) to compile a mutational spectrum. This was compared with a NSBC spectrum assembled from 118 mutations reported in the literature. The proportion of BPS at CpG dinucleotides was significantly higher in SBC than in NSBC (18/34 versus 25/103, P = 0.003). There was also a bias away from mutations in exons 7 and 8 towards mutations in exons 5 and 6. We suggest that the excess of transitions at CpG dinucleotides in SBC results from nitric oxide (NO) produced by the inflammatory response provoked by schistosomal eggs. NO could produce such mutations directly, by deamination of 5-methylcytosine, and indirectly, following conversion to nitrate, bacterial reduction to nitrite and endogenous formation of urinary N-nitroso compounds. These produce O6-alkylguanines in DNA, leading to very high rates of G:C-->A:T transitions, a process possibly augmented by inefficient repair of alkylated bases at CpG dinucleotides.

Adenocarcinoma↗
PubMed1995

Formation of 8-nitroguanine by the reaction of guanine with peroxynitrite in vitro.

Nitric oxide and superoxide anion, both formed in inflamed tissues, react rapidly to form the peroxynitrite anion (ONOO-), a strong oxidant which can initiate reactions characteristic of hydroxyl radical (HO.), nitronium ion (NO2+) and nitrogen dioxide radical (NO2.). Peroxynitrite, therefore, may cause DNA or tissue damage, contributing to the multistage carcinogenesis process. We have studied reactions of various bases, nucleosides or deoxynucleosides with peroxynitrite in vitro. Guanine reacted rapidly with peroxynitrite under physiological conditions and formed several substances, two of which were yellow, a characteristic of nitro and nitroso compounds. On the basis of chromatographic and spectral evidence we identified the major compound (which accounts for approximately 80% of all compounds formed) as 8-nitroguanine. Its formation was maximal at approximately pH 8 and increased dose-dependently with peroxynitrite concentration, but was not dependent on guanine concentration. The presence of ferric ions, which has been shown to catalyse nitration of tyrosine, did not affect nitration of guanine. 8-Nitroguanine could act as a specific marker for DNA damage induced by peroxynitrite in inflamed tissues.

Carcinogens↗
PubMed1996

Characterization of bacterial cytochrome cd(1)-nitrite reductase as one enzyme responsible for catalysis of nitrosation of secondary amines.

Bacterial formation of carcinogenic N-nitroso compounds may play a role in the etiology of human cancer. Biochemical and immunological studies in denitrifying bacteria (Pseudomonas aeruginosa) strongly support the identification of cytochrome cd(1)-nitrite reductase as the enzyme responsible for the catalysis of nitrosation through the production of nitric oxide or NO(+)-like species. Interestingly, electron paramagnetic resonance studies have shown that large quantities of nitric oxide or NO(+)-species were also produced by non-denitrifying enterobacteria (Escherichia coli, Proteus morganii).

Antibodies↗
PubMed1996

Mutation in the p53 tumor suppressor gene in rat esophageal papillomas induced by N-nitrosomethylbenzylamine.

Mutations in the p53 tumor suppressor gene have been implicated in the pathogenesis of a wide variety of human neoplasms. The location and types of p53 gene mutation can reflect exposure of humans to certain types carcinogenic agents. Much less is known about the role of p53 mutational inactivation in rodent tumors. Using both 'Hot' (radioactive) and 'Cold' (non-radioactive) single strand conformation polymorphism (SSCP) analyses, the present study of analyzed exons 5-8 and the exon-intron junction of the p53 gene from rat esophageal papillomas induces by N- nitrosomethylbenzylamine (NMBA) for mutations. Nine of 30 (30%) esophageal papillomas contained SSCP mobility shifts, principally within exons 5 and 7. These positive SSCP findings were further validated by direct DNA sequencing analysis. Eight of the nine mutations were G:C-->A:T transitions in codons 131, 149, 153, 242 (2), 243, 248, and the 5 end of intron 7. None of these G:C-->A:T mutations occurred at the CpG sites. The other mutation was a frameshift mutation in codon 176. The G:C-A:T transitions observed in this study are consistent with the documented formation of O(6)-methylguanine adducts in DNA N-nitroso compounds. These results suggest that point mutations of the p53 gene are involved in the development of approximately one-third of NMBA-induced rat esophageal papillomas. 'Hot' and 'Cold' SSCP methods were equally sensitive for the identification of mutations in the rat p53 gene.

Animals↗