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PubMed1986

Relevance of N-nitrosamines to esophageal cancer in China.

Studies on the relevance of the N-nitrosamines to esophageal cancer in China are reviewed. Esophageal cancer is a complex and multifactorial problem. Although a causal association between nitrosamines exposure and esophageal cancer in China has not yet been rigorously established, exposure of Lin-Xian subjects to nitrosamines either directly or as a result of their in vivo formation has been detected in our study. Several N-nitrosamines (NDMA, NDEA, NMBzA, NPyr, NPip, and NSAR) in gastric juice collected from Lin-Xian inhabitants have been detected. A correlation was found between the lesions of esophageal epithelium and the amount of nitrosamines present. In addition, the amounts of N-nitrosamino acids (N-nitrosoproline, N-nitrosothiazolidine 4-carboxylic acid, NSAR, and nitrates) excreted in 24-hr urine of subjects in Lin-Xian were significantly higher than those in Fan-Xian, indicating a higher exposure to N-nitroso compound and their precursors of the inhabitants in the high-risk area. The effect of nitrosamines on human esophagus has been investigated at the cellular levels. The amounts of O6-MedG in DNA of esophageal or stomach mucosa of patients from Lin-Xian were higher than that from Europe (Lyon and Essen). The presence of O6-MedG in the human fetal esophagus cultured with NMBzA was also detected. These findings indicate that the elevated levels of O6-MedG in esophageal DNA could be the result of a recent exposure to N-nitroso compounds or a genetically determined reduced cellular capacity for repair of O6-MedG from DNA. The hyperplasia was induced in the esophagus of human fetus that cultured with NMBzA for 2 weeks to 2 months. The intervention studies of esophageal cancer in Lin-Xian have been pursued. Intake of moderate doses of ascorbic acids by Lin-Xian subjects effectively reduced the urinary levels of N-nitrosamino acids to those found in un-dosed subjects in the low-risk area. If N-nitroso compounds are formed in vivo and are among the causative factors of esophageal cancer in Lin-Xian, ascorbic acid appears to be effective in lowering the body burden of these carcinogenic compounds. Thus, the plan of chemoprevention is carried out in Lin-Xian.

Ascorbic Acid↗
PubMed2005

Selective photo-reduction of N-nitroamines combined with micellar electrokinetic chromatography and laser fluorimetric detection.

N-nitroso compounds (NOC) are potent carcinogens. Reliable methods for the analysis of volatile carcinogenic NOC are well established; however selective and sensitive methods for routine analysis of thermally unstable, ionic or non-volatile NOC are still needed. For this purpose, a method based on micellar electrokinetic chromatography (MEKC) with laser induced fluorescence (LIF) detection is described for the simultaneous determination of a broad range of N-nitroso compounds. In this procedure, the nitroso group is photolytically cleaved from the NOC to yield the corresponding amine. The amines are then derivatized with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl), identified and quantified using MEKC-LIF. For the standard mixture of NOC, this method has good sensitivity and a large dynamic range. The detection limit provided by the method is 9 ppb for N-nitrosopyrrolidine.

4-Chloro-7-nitrobenzofurazan↗
PubMed2006

Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).

Vitamin C is an antioxidant and inhibitor of carcinogenic N-nitroso compound production in the stomach. Higher dietary vitamin C consumption is associated with decreased risk of gastric cancer (GC) in numerous case-control studies, but data from prospective studies are limited, particularly so for blood measures of vitamin C. The objective of this study was to determine the association of plasma and dietary vitamin C levels with the risk of GC in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 European countries. Using a fluorometric method, vitamin C was measured in pre-diagnostic plasma from 215 GC cases (matched controls = 416). Conditional logistic regression models adjusted by body mass index, total energy intake, smoking status/duration/intensity and Helicobacter pylori infection status were used to estimate relative cancer risks. No association with GC risk was observed for dietary vitamin C, whereas an inverse GC risk was observed in the highest versus lowest quartile of plasma vitamin C [odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.31-0.97, P(trend) = 0.043], which was maintained after exclusion of cases with <or=2 years follow-up (OR = 0.40, 95% CI = 0.19-0.83, P(trend) = 0.064). The inverse association was more pronounced in subjects consuming higher levels of red and processed meats, a factor that may increase endogenous N-nitroso compound production. The effect of plasma vitamin C was not different by GC anatomical subsite (cardia/non-cardia) or histological subtype (diffuse/intestinal), and there was no significant interaction of effect with H.pylori. The results of this study show, in a prospective setting, an inverse association of GC risk with high levels of plasma vitamin C and suggest an interaction with the intake of red and processed meats, whose consumption may elevate endogenous N-nitroso compound production.

Aged↗
PubMed1994

Reactions of oxidatively activated arylamines with thiols: reaction mechanisms and biologic implications. An overview.

Aromatic amines belong to a group of compounds that exert their toxic effects usually after oxidative biotransformation, primarily in the liver. In addition, aromatic amines also undergo extrahepatic activation to yield free arylaminyl radicals. The reactive intermediates are potential promutagens and procarcinogens, and responsible for target tissue toxicity. Since thiols react with these intermediates at high rates, it is of interest to know the underlying reaction mechanisms and the toxicologic implications. Phenoxyl radicals from aminophenols and aminyl radicals from phenylenediamines quickly disproportionate to quinone imines and quinone diimines. Depending on the structure, Michael addition or reduction reactions with thiols may prevail. Products of sequential oxidation/addition reactions (e.g., S-conjugates of aminophenols) are occasionally more toxic than the parent compounds because of their higher autoxidizability and their accumulation in the kidney. Even after covalent binding of quinone imines to protein SH groups, the resulting thioethers are able to autoxidize. The quinoid thioethers can then cross-link the protein by addition to neighboring nucleophiles. The reactions of nitrosoarenes with thiols yield a so-called "semimercaptal" from which various branching reactions detach, depending on substituents. Compounds with strong pi-donors, like 4-nitrosophenetol, give a resonance-stabilized N-(thiol-S-yl)-arylamine cation that may lead to bicyclic products, thioethers, and DNA adducts. Examples of toxicologic implications of the interactions of nitroso compounds with thiols are given for nitrosoimidazoles, heterocyclic nitroso compounds from protein pyrolysates, and nitrosoarenes. These data indicate that interactions of activated arylamines with thiols may not be regarded exclusively as detoxication reactions.

Amines↗
PubMed1996

A comparative study on the effect of MNU on human lymphocyte cultures in vitro evaluated by O6-mdG formation, micronuclei and sister chromatid exchanges induction.

N-Nitroso-compounds are a large group of chemicals present in a number of environmental sources and many of them are mutagens as well as carcinogens in experimental animals. Among the known N-nitroso-compounds, N-nitroso-N-methylurea (MNU) is a strong mutagen. In this study an effort has been made to compare the ability of MNU to methylate the O6-guanosine site in DNA and to induce micronuclei and sister chromatid exchanges in human lymphocyte cultures in vitro. To quantitate O6-methyldeoxyguanosine (O6-mdG) a highly sensitive immunoassay, immuno-slot-blot (ISB), has been used. For the evaluation of micro nuclei (MN) the cytokinesis block micronucleus method has been used. Different concentrations (75, 100, 125 micrograms/ml) were tested. At the highest concentration tested for the MN induction, 125 micrograms/ml, the occurrence of binucleates and micro nuclei is higher than twice in relation to control and a reduction in NDI is also observed. The same concentrations were used for the estimation of sister chromatid exchanges (SCEs) induction. The mean number of SCEs at 125 micrograms/ml is almost three times that of the control level. The concentrations tested for the quantitation of O6-mdG were 200, 300 and 400 micrograms/ml and this was done because for the test system we used and for the given experimental conditions the first indication of O6-mdG formation was at 200 micrograms/ml. Our results show that methylation of O6-guanosine increases with concentration and at 400 micrograms/ml the concentration of O6-mdG is 5.83 fmol/microgram DNA, while at the control level it is 2.40 fmol/microgram DNA. Since O6-mdG formation is observed in higher concentrations than those of MN and SCE induction it would be interpreted that O6-mdG levels are not correlated with the studied cytogenetic effects although one has to take into consideration the total promutagenic lesions in DNA, induced by MNU, as well as AGT repair activity.

Carcinogens↗
PubMed1988

Cytochrome P-455 nm complex formation in the metabolism of phenylalkylamines. IX. A comparative study with enantiomeric 2-nitroso-1-phenylpropane in microsomes and a reconstituted cytochrome P-450 system from rat liver.

Formation of cytochrome P-455 nm complexes was investigated with enantiomeric 2-nitroso-1-phenylpropane--the C-nitroso analogue of amphetamine--and optically active N-hydroxyamphetamine, in the presence of NADPH. For comparative reasons, three different drug-metabolizing enzyme systems were used, namely microsomes from control and phenobarbital-treated rats, and a reconstituted system containing the main phenobarbital-induced form of cytochrome P-450 from rat liver. In microsomes obtained from phenobarbital-treated rats, pronounced differences in the kinetics of complex formation were observed between the enantiomeric C-nitroso compounds, but not between the isomers of N-hydroxyamphetamine. In the reconstituted enzyme system the S-nitroso compound formed the P-455 nm chromophore at the highest initial rate, while the R analogue was devoid of complexing activity. The rates of complex formation from the N-hydroxylamine enantiomers were high and equal.

Animals↗
PubMed1988

Alkylating activity in food products--especially sauerkraut and sour fermented dairy products--after incubation with nitrite under quasi-gastric conditions.

N-Nitroso compounds may well rank high among the genotoxic carcinogens present in our environment. Small amounts of such compounds may be formed in the human stomach after consumption of high-nitrate vegetables. Volatile nitrosamines can be conveniently determined but reliable methods of analysis for non-volatile N-nitroso compounds are still lacking. In this study we have used the 4-(4-nitrobenzyl)pyridine test to look for the formation of alkylating compounds such as N-nitroso-N-methylurea in a wide range of food products after incubation with nitrite under simulated gastric conditions. Our results indicate that many food products do not form alkylating compounds in appreciable amounts, even though the nitrite concentration used was five to ten times that found in saliva after a high-nitrate meal. Comparatively strong alkylating activity, however, was detected after incubation of samples of sauerkraut, certain dairy products (yoghurt, biogarde, quark, buttermilk and milk), wine and smoked mackerel. Samples of sauerkraut incubated with simulated gastric fluid, but without (added) nitrite, also displayed appreciable alkylating activity. The formation of alkylating substances in non-fat yoghurt was markedly inhibited by addition of ascorbic acid. The identity of the alkylating agents remains unknown. The isolation procedure was optimized for N-nitroso-N-methylurea, but will certainly result in the isolation of other compounds, such as C-nitroso-, C-nitro- or perhaps even C-nitroso-C'-nitro-compounds as well. Biogenic amines, glucosinolates, indole derivatives or other compounds may be involved as precursors. If alkylating agents are formed in vivo after ingestion of high-nitrate vegetables or drinking water, this is likely to occur only when the food products mentioned above are ingested simultaneously with or shortly after the nitrate load and not appreciably (except perhaps in the case of sauerkraut) when they are ingested alone, without a nitrate source. The health implications of these findings cannot yet be established. Many alkylating agents, however, have strong carcinogenic properties and continued investigation of food products (and their interaction products with nitrite) is indicated.

Alkylating Agents↗
PubMed1986

Mutagenicity of para-nitroso-dimethyl- and diethyl-anilines.

Low concentrations of para-nitroso-dimethylaniline (NdMA) were mutagenic to Salmonella typhimurium TA100 with optimal effect at 1.5 microM in fluctuation assays, without activating enzymes. The diethyl homologue (NdEA) had little or no mutagenic effect at low concentrations, although the bacteriocidal effects of NdMA and NdEA were similar. At higher bacteriocidal concentrations (approximately LC55-LC80) both NdMA and NdEA were mutagenic. NdMA and some other C-nitroso compounds proved carcinogenic in animal bioassays, and further research is needed to assess the human hazard from exposure to C-nitroso compounds in food, medicines or industry.

Mutagenicity Tests↗
PubMedDate not supplied

Risk factors for astrocytic glioma and primitive neuroectodermal tumor of the brain in young children: a report from the Children's Cancer Group.

We conducted a matched case-control study to investigate risk factors for the two most common types of brain tumors in children, astrocytic glioma and primitive neuroectodermal tumor (PNET). Since the study focused on gestational exposures, we restricted it to young children because these exposures would be expected to act early in life. Parents of 155 astrocytic glioma cases, 166 PNET cases, and controls identified by random digit dialing completed telephone interviews. Few associations occurred with the hypothesized risk factors, which were gestational exposure to alcohol, hair coloring products, farms, and substances containing N-nitroso compounds (passive smoking, makeup, incense, new cars, pacifiers, baby bottles, beer). Of the products studied that contain N-nitroso compounds, only beer was associated with a significantly increased risk of either tumor type [odds ratio (OR) for PNET = 4.0; 95% confidence interval (CI), 1.1-22.1; P = 0.04]. Elevated ORs for PNET were observed for farm residence of the mother during the pregnancy (OR = 3.7; 95% CI, 0.8-23.9; P = 0.06) and of the child for at least a year (OR = 5.0; 95% CI, 1.1-46.8; P = 0.04). Significant associations with astrocytoma were observed for mother's use of kerosene (OR = 8.9; 95% CI, 1.1-71.1; P = 0.04) and birth by Caesarean section (OR = 1.8; 95% CI, 1.1-3.2; P = 0.03). History of miscarriage was associated with a lower risk of PNET (OR = 0.5; 95% CI, 0.3-0.9; P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Abortion, Spontaneous↗
PubMed1994

Maternal diet and risk of astrocytic glioma in children: a report from the Childrens Cancer Group (United States and Canada)

N-nitroso compounds and their precursors, nitrites and nitrates, have been hypothesized as risk factors, and vitamins C and E, which inhibit N-nitroso formation, as protective factors for brain tumors. A case-control study of maternal diet during pregnancy and risk of astrocytoma, the most common childhood brain tumor, was conducted by the Childrens Cancer Group. The study included 155 cases under age six at diagnosis and the same number of matched controls selected by random-digit dialing. A trend was observed for consumption of cured meats, which contain preformed nitrosamines (a class of N-nitroso compounds) and their precursors (adjusted odds ratio [OR] for highest quartile of intake relative to lowest = 1.7, P trend = 0.10). However, no strong trends were observed for nitrosamine (OR = 0.8, P = 0.60); nitrite (OR = 1.3, P = 0.54); nitrate (OR = 0.7, P = 0.43); vitamin C (OR = 0.7, P = 0.37); or vitamin E (OR = 0.7, P = 0.48). Iron supplements were associated with a significant decrease in risk (OR = 0.5, 95 percent confidence interval = 0.3-0.8). The effect of several dietary factors differed by income level, making interpretation of the results difficult. Future research should investigate the effect of dietary components not assessed in this study, as these may explain the disparate effects by income level. The results of this study provide limited support for the nitrosamine hypothesis.

Astrocytoma↗
PubMed1997

Evaluation of the rodent micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the summary report of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus Group Test. Mammalian Mutagenicity Study Group.

To assess the correlation between micronucleus induction and human carcinogenicity, the rodent micronucleus assay was performed on known and potential human carcinogens in the 6th MMS/CSGMT collaborative study. Approximately 100 commercially available chemicals and chemical groups on which there was little or no micronucleus assay data were selected from IARC (International Agency for Research on Cancer) Groups 1 (human carcinogen), 2A (probable human carcinogen) and 2B (possible human carcinogen). As minimum requirements for the collaborative study, 5 male mice were treated by intraperitoneal injection or oral gavage once or twice with each chemical at three dose levels, and bone marrow and/or peripheral blood was analyzed. Five positives and 2 inconclusives out of 13 Group 1 chemicals, 7 positives and 5 inconclusives of 23 Group 2A chemicals, and 26 positives and 6 inconclusives of 67 Group 2B chemicals were found. Such low positive rates were not surprising because of a test chemical selection bias, and we excluded well-known micronucleus inducers. The overall evaluation of the rodent micronucleus assay was based on the present data combined with published data on the IARC carcinogens. After merging, the positive rates for Groups 1, 2A and 2B were 68.6, 54.5 and 45.6%, respectively. Structure-activity relationship analysis suggested that the micronucleus assay is more sensitive to the genetic toxicity of some classes of chemicals. Those to which it is sensitive consist of (1) aziridines and bis(2-chloroethyl) compounds; (2) alkyl sulfonate and sulfates; (3) acyl-type N-nitroso compounds; (4) hydrazines; (5) aminobiphenyl and benzidine derivatives; and (6) azo compounds. Those to which it is less sensitive consist of (1) dialkyl type N-nitroso compounds; (2) silica and metals and their compounds; (3) aromatic amines without other functional groups; (4) halogenated compounds; and (5) steroids and other hormones. After incorporation of structure-activity relationship information, the positive rates of the rodent micronucleus assay became 90.5, 65.2 and 60.0% for IARC Groups 1, 2A and 2B, respectively. Noteworthy was the tendency of the test to be more sensitive to those carcinogens with stronger evidence human carcinogenicity.

Animals↗
PubMed1981

Evidence for a food additive as a cause of ketosis-prone diabetes.

A comprehensive survey of ketosis-prone diabetes showed a 29% preponderance of males and a trend for the time of diagnosis to coincide with epidemics of viral diseases. There was a significantly increased incidence between July and January in the age group diagnosed at 0-14 years but this seasonal trend was not shown in a group of boys diagnosed at this age who were all born in the month of October. The incidence of diabetes in this group of boys was very much higher than would be expected (p less than 0.00001). HLA histocompatibility types and virus infections were considered as possible causes of this striking finding but there seemed to be at least one additional seasonal factor acting prenatally. Circumstantial evidence suggested that this additional factor is the N-nitroso-compound content of processed mutton traditionally consumed in Iceland in the two weeks from December 23. Recently produced Icelandic smoked/cured mutton contains considerable concentrations of N-nitroso-compounds. This work implies that a common food additive contributes to the production of ketosis-prone diabetes, not in the consumer but in the progeny.

Adolescent↗
PubMed1984

Amadori- and N-nitroso-Amadori compounds and their pyrolysis products. Chemical, analytical and biological aspects.

N-(1-Deoxy-D-fructos-1-yl)-L-amino acids (fructose amino acids), Amadori compounds, are formed by reaction of D-glucose and L-amino acids and Amadori rearrangement. They are detected in heat-processed natural products and various foodstuffs and are key products of the Maillard-Browning reaction. N-Nitroso-N-(1-deoxy-D-fructos-1-yl)-L-amino acids (N-NO-fructose amino acids), N-NO-Amadori compounds, are formed in high yields by reacting fructose amino acids with sodium nitrite in acidic aqueous solution. They constitute a new class of non-volatile, bis-beta-oxidized nitrosamine derivatives with unknown biological (mutagenic and/or carcinogenic) activity. N-NO-Fructose amino acids may be formed in nitrite-containing Maillard systems (e.g., cured-meat products, tobacco) or in the human stomach after ingestion of food containing fructose amino acids and nitrite in food or saliva. Thirteen fructose amino acids and 13 N-NO-fructose amino acids (-gly, -ala, -val, -leu, -ileu, -ser, -thr, -met, -asp, -pheala, -tyr, -his, -trp) were prepared and investigated by high-resolution 1H-nuclear magnetic resonance (NMR) and 13C-NMR spectroscopy. The percentage amounts of the sugar ring forms (beta-pyranose, beta-furanose, alpha-furanose and alpha-pyranose) of these compounds in D2O mutarotation equilibrium were determined by 13C-NMR spectroscopy, together with the amounts (%) of E/Z isomers in the case of N-NO-compounds. The nitrosation products of D-fru-L-tyr, D-fru-L-his and D-fru-L-trp were isolated and identified by spectroscopic methods (NMR, infra-red). The N-NO-fructose amino acids can be separated by reversed-phase, ion-pairing, high-performance liquid chromatography. In some case the E/Z isomers are separated.

Amino Acids↗
PubMed1977

Nitrosamines and nitrosamides in the etiology of gastrointestinal cancer.

It has been amply demonstrated that N-nitroso compounds are formed by interaction of nitrite with secondary and tertiary amino compounds, and that this reaction can occur in vivo as well as in food processed with nitrite. The favored site of reaction in vivo is the stomach. It is likely that N-nitroso compounds formed in this way, especially nitrosamides, could reach the colon and contribute to the induction of colon tumors.

Amides↗
PubMed1992

Identification of metabolites of 4,4'-diaminodiphenylmethane (methylene dianiline) using liquid chromatographic and mass spectrometric techniques.

The in vitro metabolism of 4,4'-diaminodiphenylmethane (methylene dianiline, MDA) was investigated using rabbit liver microsomes. Minimal clean-up of the microsomal incubations was carried out using zinc sulphate precipitation followed by solid-phase extraction on Sep-Pak C18 cartridges. Three metabolites were detected in hepatic microsomal incubations, namely the azodiphenylmethane (azo) azoxydiphenylmethane (azoxy) and 4-nitroso-4'-aminodiphenylmethane (nitroso) compounds. The azo and azoxy metabolites were produced enzymatically whereas the nitroso compound may have been formed via a non-enzymatic process. Reversed-phase high-performance liquid chromatography-plasma spray mass spectrometry was used to initially detect these metabolites. Fast atom bombardment mass spectrometry and fast atom bombardment tandem mass spectrometry were utilized to further structurally characterise these compounds. Comparison of mass spectral data obtained from synthesised standards with data obtained on the putative metabolites substantiated the characterisation of these compounds.

Aniline Compounds↗
PubMed1991

Mutagenicity of nitrosated food items.

Several food items, commonly consumed in South India, after nitrite treatment under simulated gastric conditions were found to be mutagenic in Salmonella typhimurium tester strain TA 100. Dichloromethane extracts containing the volatile nitroso compounds and ethyl-acetate extracts with the non-volatile nitroso compounds of some of the food items exhibited mutagenicity.

Animals↗
PubMed1975

Nitrosation of phenacetin. Formation of N-nitroso-2-nitro-4-ethoxyacetanilide as an unstable product of the nitrosation in dilute aqueous-acidic solution.

Reaction of phenacetin with N2O4 in glacial acetic acid at 10(0) C gives N-nitroso-2-nitro-4-ethoxyacetanilide. This N-nitrosoacylarylamine is stable at low temperatures (--30 degress C) but unstable at ambient temperature. No intact N-nitroso-2-nitro-4-ethoxyacetanilide can be detected when phenacetin is nitrosated under conditions simulating those in the stomach (37 degrees C, pH 1). Instead, 2-nitro-4-ethoxybenzenediazonium chloride is the main reaction product found. Under the conditions applied, the N-nitrosoacylarylamine rapidly rearranges by 1,3-migration of the acetyl group. The resulting diazoester dissociates into the corresponding diazonium salt. Trapping of the diazonium ion with 1-naphthol as an azo dye provides a useful means to identify the parent N-nitroso compound and to measure colorimetrically its rate of formation. The yields obtained in dilute aqueous nitrosation mixtures are lower than expected; the reasons for this finding are discussed. Preliminary results of animal experiments show that the N-nitroso compound is a directly acting carcinogen.

Acetanilides↗
PubMed1988

Superoxide dismutase-mediated reversible conversion of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole, the N-hydroxy derivative of Trp-P-2, into its nitroso derivative.

Aerobic oxidation of 3-hydroxyamino-1-methyl-5H-pyrido-[4,3-b]indole [Trp-P-2(NHOH)] in neutral aqueous solution was greatly accelerated by copper-zinc superoxide dismutase (SOD). The major product in this SOD-mediated reaction was identified as 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole [Trp-P-2(NO)]. This conversion was accompanied by a decrease of the mutagenicity of the mixture, as monitored by the direct-acting mutagenicity on Salmonella typhimurium TA98; a rapid change to approximately 1/3 of the original mutagenicity was followed by no further decrease of the activity. In contrast, in the spontaneous aerobic oxidation of Trp-P-2-(NHOH), the mutagenicity slowly and continuously decreased, until it was finally lost almost completely. Similar acceleration by SOD of aerobic oxidation was found for 2-hydroxyamino-6-methyldipyrido[1,2-a:3',2'-d]imidazole [Glu-P-1(NHOH)]. Again, mutagenicity of approximately 1/4 that of the original was retained in the SOD-mediated decomposition, while a complete loss of the mutagenicity was observed in the spontaneous decomposition. When Trp-P-2(NO) was treated with the superoxide-generating system, xanthine oxidase plus xanthine, Trp-P-2(NHOH) was formed. Therefore, the role of SOD in the conversion of Trp-P-2(NHOH) into Trp-P-2(NO) is the removal of superoxide anions generated by reduction of aerobic oxygen, thereby inhibiting the reverse reactions, i.e. the reduction of Trp-P-2(NO) and that of the putative intermediate nitroxide radical. In support of this proposed mechanism, phenylhydroxylamine underwent a SOD-accelerated conversion to nitrosobenzene, and nitrosobenzene was reduced to phenylhydroxylamine by the action of the xanthine oxidase-xanthine system. Hence, this reversible interchange between an arylhydroxylamine and its nitroso compound, coupled with the oxygen-superoxide cycle, may be a general phenomenon. A consequence of this finding is that the xenobiotic N-hydroxylamines may be converted by the action of SOD in the biological settings into nitroso compounds, which are chemically more stable, serving as a reservoir for mutagenicity.

Carbolines↗