Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Humans are exposed not only to preformed N-nitroso compounds (NOC) but also to a wide range of nitrogen-containing compounds and nitrosating agents which can react in vivo to form NOC, a versatile class of carcinogens. Nitrosating agents and NOC can also be synthesized endogenously in reactions mediated by bacteria and activated macrophages. Thus, endogenous formation of NOC can occur at various sites in the body. A sensitive procedure (the N-nitrosoproline (NPRO) test) has been developed to estimate exposure of humans to exogenous and endogenous NOC. Results of studies in human subjects with this test led to the following conclusions: (1) The process of endogenous nitrosation in humans is influenced by many factors; therefore, determination only of nitrate and nitrite in body fluids is insufficient to assess the extent of nitrosation in man in vivo. (2) In clinical studies to examine the model of gastric carcinogenesis based on bacterial colonization and nitrosation in vivo, progress has been made in explaining some steps, but several controversies remain. Although bacterial strains possessing enzymes that catalyse N-nitrosamine formation at neutrality have been isolated from the gastric juice of achlorhydric subjects, their precise role in gastric carcinogenesis remains to be clarified. (3) Formation of endogenous NOC was assessed by the NPRO test in: (i) subjects living in high- and low-incidence areas for stomach cancer in northern Japan, Costa Rica and Poland; (ii) subjects with different habits of betel-quid chewing and tobacco use; (iii) patients with urinary bladder infections; and (iv) subjects infested with liver fluke in Thailand. In all instances, greater exposure to endogenous NOC was found in high-risk subjects, but individual exposure was greatly affected by dietary modifiers of disease state: ascorbic acid efficiently lowered the body burden of intragastrically formed NOC. (4) Increased nitrosation is also observed in tobacco smokers, adding to the body burden of ingested or inhaled tobacco-related carcinogens. These results, together with the knowledge that NOC produce tumours in 40 animal species, clearly underline the potential role of NOC (and other nitrite-reactive compounds) in human cancer etiology, particularly when exposure starts early in life and persists over a long period. The demonstrated efficacy of certain vitamins as nitrosation inhibitors also provides a plausible interpretation of epidemiological findings that have shown protective effects of fruits and vegetables (sources of vitamins and polyphenols) against various malignancies and particularly stomach cancer.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:N-nitroso compounds and human cancer: where do we stand? 185 28

The concentrations of nitrite, thermo- and acetic acid-labile TEA-responsive compounds (TACs) and N-nitroso compounds (NOCs) as a group were measured in human gastric juice collected just before and 1, 2 and 4 h after oral ingestion of 1 g ascorbic acid (AA) or 200 mg sodium nitrate, separately or in combination. Individual responses of gastric [nitrite] following ingestion of AA alone varied widely, with both decreases and increases being observed, and showed no correlation with gastric pH. While a mixed response was also noted for [NOC] and [TAC], substantial decreases were observed in 5/6 individuals with initial [NOC] greater than 0.2 microM and 3/3 individuals with initial [TAC] greater than 0.2 microM, implying that (i) AA effectively inhibited gastric nitrosation and (ii) a basal amount of NOCs and TACs was present in gastric juice which could not be lowered by AA ingestion. Statistical analysis indicated that global mean values of gastric [NOC] were significantly reduced (P less than 0.02) 1-4 h after ingestion of AA. Ingestion of 200 mg sodium nitrate alone resulted in increases in gastric [NOC], which in some cases were very substantial. While nitrosation appeared lower following ingestion of the same dose of nitrate in combination with 1 g AA, the difference from the effects of nitrate alone was not statistically significant. In aqueous buffer, pH 2.5, and in the presence of 1 mM AA, 50 microM nitrite was consumed with a t1/2 of 50 min only if molecular oxygen had first been removed from the system. In the presence of oxygen, no consumption of nitrite could be detected in 50 min, reflecting nitrite recycling (oxidation of nitric oxide to higher oxides of nitrogen and hydrolysis back to nitrite). It is likely that nitrite recycling occurring after collection of gastric juice accounted for the inconsistent responses of gastric nitrite following ingestion of AA. Incubation of human gastric juice, pH 2.5, in vitro in the presence of 50 microM sodium nitrite for 60 min resulted in an increase of [NOC] and [TAC] from 0.10 to 0.70 and 1.10 microM respectively. Nitrosation was efficiently inhibited by AA, 2.27 mM AA resulting in 87 and 100% inhibition respectively. Removal of oxygen from the reaction mixture did not have any significant effect on the extent of nitrosation in the presence or absence of AA.
Carcinogenesis 1991 Aug
PMID:Studies in gastric carcinogenesis. V. The effects of ascorbic acid on N-nitroso compound formation in human gastric juice in vivo and in vitro. 186 Jan 56

Analytical epidemiology techniques were used to study the malignant neoplasms prevalence in the population of Magnitogorsk (400,000), and among the workers engaged in the Magnitogorsk metallurgical plant (64,000 workers). Revealed was that the malignant neoplasms related morbidity rate was 1.6 higher in men and 3.2 higher in women among the plant workers as compared with the city population in general. The cancer risk factors were predominantly occupational ones, e. i. the major industrial carcinogens--benzopyrene in tars and carbon-black; benzol, chromium and nickel in the dust; the carcinogenesis modifying substances--nitrogen oxide, sulfur dioxide, phenols, iron oxides, lead and its non-organic compounds, high temperatures. The data received can be used in further studies and elaboration of primary preventive measures.
 ...
PMID:[Comparative analysis of oncological morbidity in the population of an industrial city and workers of a metallurgical plant]. 186 76

In contrast to 1-nitropyrene (1-NP), which is the most abundant nitropolycyclic aromatic hydrocarbon in numerous environmental sources, 2-nitropyrene (2-NP) has been detected only in the ambient air and not in direct emissions. Thus, 2-NP can be used as an indicator for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Therefore, it is essential to determine the possible metabolic pathways of 2-NP. The metabolism of 2-NP by rat liver 9000 g supernatant was investigated. Under aerobic conditions, ring oxidation to 6-hydroxy-2-nitropyrene and nitroreduction to 2-aminopyrene (2-AP) were observed. When incubations were carried out in an atmosphere of nitrogen, 2-AP was the only metabolite detected. These results are consistent with those observed with 1-NP. In vitro metabolic activation of 2-NP to DNA adducts catalyzed by xanthine oxidase was also examined. Two adducts were characterized as N-(deoxyguanosin-8-yl)-2-aminopyrene and N-(deoxyadenosin-8-yl)-2-aminopyrene. The presence of deoxyadenosine adduct, which is derived from the nitroreduction pathway, may contribute to the powerful direct-acting mutagenicity of 2-NP.
Carcinogenesis 1991 Mar
PMID:Identification of the major metabolites and DNA adducts formed from 2-nitropyrene in vitro. 200 92

Previous studies have demonstrated that three cancer chemotherapeutic compounds of the nitrogen mustard class, melphalan (L-PAM), nitrogen mustard (HN2) and chlorambucil (CBC), each generated DNA lesions that prematurely terminate in vitro transcription. Sites of these lesions were inconsistent with sites of N7 guanine monoadducts formed by these compounds, and in the cases of L-PAM and CBC were suggestive of adenine lesions. The present study is an attempt to identify and characterize nitrogen mustard-induced non-N7 guanine DNA adducts, and in particular adenine DNA adducts, and to assess their role in drug-induced in vitro transcription termination. Data from studies using a modified Maxam-Gilbert DNA sequencing technique demonstrate that L-PAM and CBC, but not HN2, generate heat-labile, alkaline-stabilized adenine adducts at nearly every adenine in a region of a defined DNA template examined. Comparison of sites of L-PAM- and CBC-induced adenine adducts to known sites of drug-induced transcription termination in the same DNA template show that L-PAM- and CBC-induced transcription termination is associated not with drug lesions at single adenines, but rather with drug-induced adducts at neighboring adenines. Additional in vitro transcription studies using a small DNA molecule generated by polymerase chain reaction-mediated DNA amplification demonstrate that none of the transcription-terminating lesions induced by L-PAM and CBC in this molecule are interstrand in nature. These results suggest that some, but not all, nitrogen mustard compounds can generate heat-labile adenine lesions in DNA, and that bifunctional nitrogen mustards that can form heat-labile adenine adducts also form adducts consistent with intrastrand adenine-adenine crosslinks. These adducts at pairs of adenines in turn appear to be responsible for L-PAM- and CBC-induced transcription termination in vitro.
Carcinogenesis 1990 Oct
PMID:DNA adenine adducts induced by nitrogen mustards and their role in transcription termination in vitro. 220 89

Hemoglobin adducts of aromatic amines released from pesticides were investigated. Female Wistar rats were dosed orally with pesticides up to 1 mmol/kg body weight. Blood was obtained after 24 h, hemoglobin isolated and hydrolyzed in 1 NaOH. The amines were extracted and quantified by gas chromatography with nitrogen-specific or mass-selective detection. The following binding indices [HBI, hemoglobin binding index = binding (mmol/mol Hb) per dose (mmol/kg)] were obtained: pesticide (arylamine): linuron, diuron (3,4-dichloroaniline) 0.8 and 4.5 respectively; monuron, monolinuron (4-chloroaniline) 39 and 55 respectively; chlorpropham (3-chloroaniline) 2.9; chlordimeform (4-chloro-o-toluidine) 2.4; propham (aniline) 2.4. With vinclozoline and iprodione (3,5-dichloroaniline) and quintozene (pentachloroaniline) no adducts could be found. The results demonstrate the possible use of arylamine-hemoglobin adducts for measuring the bioavailability of potentially hazardous components of pesticides and the extent to which they are formed and metabolically activated.
Carcinogenesis 1990 Jan
PMID:Biomonitoring of arylamines: hemoglobin adducts of urea and carbamate pesticides. 229 19

Gaseous nitric oxide (NO) and nitrogen dioxide (NO2) were tested for their potential to induce DNA single-strand breaks (SSBs) in Chinese hamster cells (V79 cells). The alkaline elution assay was used for the detection of SSBs. V79 cells were exposed to NO and NO2 in N2 in varying concentrations (0-500 p.p.m.) and over varying periods (5-30 min). NO treatment did not result in any detectable DNA damage. NO2 led to a dose- and time-dependent increase of the rate of SSBs and the amount was dependent on concentration of NO2 and the length of exposure. The lowest observable effective concentration which was statistically different from control values was 10 p.p.m. exposed for 20 min. The metabolites of both gases, nitrite (NO2-) and nitrate (NO3-), had no DNA-damaging activity up to a concentration of 1 mM. The mechanism by which NO2 may generate SSBs is discussed.
Carcinogenesis 1990 Jan
PMID:Nitrogen dioxide induces DNA single-strand breaks in cultured Chinese hamster cells. 229 26

L-Arginine, the primary nitrogen source for nitric oxide synthesized by many cell types in culture and for biosynthesized nitrate in humans, is also a nitrogen source for biosynthesized nitrate in rats and ferrets. After administration of [15N2]L-arginine to rats and ferrets, [15N]NO3- was detected in urine. Escherichia coli lipopolysaccharide induced more than a 10-fold increase in urinary nitrate in rats and a parallel increase in incorporation of 15N from [15N2]L-arginine into NO3-. Bradykinin, a vasodilator which induces nitric oxide production by endothelial cells in vitro, lacked detectable effect on urinary nitrate or on incorporation of L-arginine nitrogen into nitrate in rats. A prolonged period of vasodilation brought on by an extended period of exercise increased urinary nitrate 2-fold in human subjects. In the rat, recoveries in 24 h post-dose urine collections of [15N]NO3- given i.v. and i.p. were 75 and 64% respectively, while in the ferret, recoveries of i.v. and per os [15N]NO3- doses were 49 and 34% respectively. Thus, nitrate synthesized by mammalian cells in vivo would undergo losses similar to those for exogenous nitrate.
Carcinogenesis 1990 May
PMID:Nitrate biosynthesis in rats, ferrets and humans. Precursor studies with L-arginine. 233 12

A major metabolic fate of 1-methyl-2-nitro-1-nitrosoguanidine (MNNG) and nitrosocimetidine (NC) in rodents is denitrosation to generate the unmodified, parent guanidinium compound. MNNG is a potent, locally-acting carcinogen. NC is the nitrosated derivative of cimetidine, an important clinical drug administered orally for the treatment of stomach ulcers. Contrary to expectations based on the results of various short-term in vitro tests for carcinogenic potential, NC is not a carcinogen when administered to rats or mice. Rat liver microsomal enzymes have been found to be capable of catalyzing the denitrosation of MNNG, NC and an NC analog, 1,3-dimethyl-2-cyano-1-nitrosoguanidine (CyanoDMNG) in an NADPH-dependent reaction. The denitrosated guanidinium compound generated accounts for 50-70% of the nitroso compound metabolized in a microsomal incubate; nitrite is generated with a yield which represents 40-60% of the guanidinium compound produced. The cytochrome P450 inhibitors metyrapone, n-octylamine, 1-n-hexylimidazole and ellipticine inhibit the conversion of CyanoDMNG to 1,3-dimethyl-2-cyanoguanidine (Cyano-DMG) and nitrite. Microsomal NADPH-cytochrome c reductase activity is not perturbed by this series of organic compound inhibitors. Diethyl maleate at high concentrations weakly stimulates the reaction. The rates of production of the CyanoDMNG degradation products CyanoDMG, nitrite and nitrate are markedly diminished in nitrogen-saturated and in carbon dioxide-saturated microsomal incubates. Preincubating microsomes for 1 h at 37 degrees C prior to substrate and NADPH addition has no effect on the denitrosation activity. Kinetic analysis of the conversion of CyanoDMNG to CyanoDMG indicates a Km of 1.0 mM and a Vmax of 2.7 nmol/min/mg protein. Microsomes isolated from rats pretreated with the cytochrome P450 inducers pyrazole or phenobarbital show enhanced denitrosation activity. The denitrosation capacity of hamster liver microsomes is similar to that observed for rat microsomes.
Carcinogenesis 1990 Jul
PMID:Microsomally-mediated denitrosation of nitrosoguanidinium compounds. 237 67

The most widely accepted metabolic pathway leading to the formation of reactive intermediates from nitrosamines involves enzymatic hydroxylation at the carbon atom alpha to the nitroso moiety. All subsequent steps are non-enzymatic reactions and the final result is the stoichiometric formation of a cationic product and molecular nitrogen. Thus the amount of molecular nitrogen evolved can be used as an indicator of alpha-hydroxylation. The use of doubly 15N-labelled nitrosamines and the detection of 15N2 by MS makes it simpler to measure the extent of alpha-hydroxylation. We have studied the alpha-oxidation of doubly 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine (BBN) and its metabolite N-nitrosobutyl(3-carboxypropyl)amine (BCPN), two potent urinary bladder carcinogens in animals, within the target organ. Various amounts of 15N-labelled BBN ranging from 0.1 to 5 mumol were incubated at 37 degrees C for 4 h in the isolated rat bladder and the formation of 15N2 was measured by GC-MS. 15N2 production was linear up to 1 mumol and represented approximately 0.1% of the substrate incubated. Time-course experiments showed that 15N2 production was linear over a 6 h incubation period, ranging from 2.16 +/- 0.05 to 4.55 +/- 0.33 nmol/mg urothelial cell protein. 15N-labelled BCPN (1-5 mumol) was also incubated within the rat isolated bladder. 15N2 production from BCPN was approximately 10 times less than that from BBN. The results indicate that, though to a lower extent, the target organ activates 15N-labelled BBN and BCPN through the alpha-hydroxylation pathway.
Carcinogenesis 1990 Aug
PMID:Alpha-oxidative metabolism of the bladder carcinogens N-nitrosobutyl(4-hydroxybutyl)amine and N-nitrosobutyl(3-carboxypropyl)amine within the rat isolated bladder. 238 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>