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S S Mirvish

Publications and source records attributed to S S Mirvish.

At least 19 recordsLinked to original sources
PubMed1995

Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC.

The questions of whether and how N-nitroso compounds (NOC) may be inducing cancer in humans are discussed. The principal subjects covered include nitrite-derived alkylating agents that are not NOC, reasons for the wide tissue specificity of carcinogenesis by NOC, the acute toxicity of nitrosamines in humans, mechanisms of in vivo formation of NOC by chemical and bacterial nitrosation in the stomach and via nitric oxide (NO) formation during inflammation, studies on nitrite esters, use of the nitrosoproline test to follow human gastric nitrosation, correlations of nitrate in food and water with in vivo nitrosation and the inhibition of gastric nitrosation by vitamin C and polyphenols. Evidence that specific cancers are caused by NOC is reviewed for cancer of the stomach, esophagus, nasopharynx, urinary bladder in bilharzia and colon. I review the occurrence of nitrosamines in tobacco products, nitrite-cured meat (which might be linked with childhood leukemia and brain cancer) and other foods, and in drugs and industrial situations. Finally, I discuss clues from mutations in ras and p53 genes in human tumors about whether NOC are etiologic agents and draw some general conclusions.

Animals↗
PubMed1995

Use of monoclonal antibodies to cytochrome P450s to indicate the critical dealkylation and the P450s involved in methyl-n-amylnitrosamine mutagenicity in the presence of induced rat liver microsomes.

The mutagenicity for Salmonella typhimurium TA 1535 of the carcinogen methyl-n-amylnitrosamine (MNAN) was examined in the presence of rat liver microsomes from uninduced and induced rats. The number of mutations followed the order phenobarbital- and Aroclor-induced > 3-methylcholanthrene- and isoniazid-induced > uninduced microsomes. The MNAN metabolite 4-hydroxy-MNAN was not mutagenic. Using each type of induced liver microsomes, we examined the effect on MNAN mutagenicity of four monoclonal antibodies (MAbs) that inhibit cytochrome P450s. The MAbs inhibited MNAN mutagenicity in seven MAb-microsome combinations by up to 49%. Taken together, these results indicated that CYP (P450) 2B1/2B2 was responsible for one half and CYP 2C11 for one quarter of MNAN mutagenicity with phenobarbital-induced microsomes, CYP 1A1/1A2 accounted for about 40% of the mutagenicity with 3-methylcholanthrene-induced microsomes, CYP 2B1/2B2 accounted for half and CYP 1A1/1A2 and 2C11 for smaller proportions of the mutagenicity with Aroclor-induced microsomes, and CYP 1A1/1A2 accounted for about 30% of the mutagenicity with isoniazid-induced microsomes. With isoniazid-induced microsomes, MAb 2-66-3 to CYP 2B1/2B1 caused an unexpected 219% increase and MAb 1-68-11 caused a moderate increase in MNAN mutagenicity. The test MAbs also inhibited the microsome-catalyzed demethylation and depentylation of MNAN by up to 83%, confirming previous results. Four comparisons between individual mutagenic and metabolic results supported the view that depentylation of MNAN was more critical for its mutagenicity than was demethylation, e.g., with 3-methylcholanthrene- and Aroclor-induced microsomes, MAb 1-7-1 to CYP 1A1/1A2 inhibited mutagenesis and depentylation, but did not affect demethylation.

Animals↗
PubMed1994

Effect of gastroduodenal juice and dietary fat on the development of Barrett's esophagus and esophageal neoplasia: an experimental rat model.

BACKGROUND: Reflux of duodenal content into the lower esophagus of rats enhances the formation of nitrosamine-induced esophageal cancer and results in the induction of adenocarcinoma. We investigated the extent of the mucosal injury that was produced when the lower esophagus of rats was exposed to the reflux of gastroduodenal juice in the presence or absence of a carcinogen and tested the hypothesis that induction of esophageal cancer in this model would be influenced by the intake of dietary fat. METHODS: Esophagoduodenostomy with gastric preservation was performed in 165 Sprague-Dawley rats in order to expose the lower esophagus to the reflux of gastroduodenal juice. Postoperatively selected groups of rats were treated with the carcinogen methyl-n-amylnitrosamine (MNAN). Subsequently, rats were fed diets of differing fat and calorie content for 20 weeks until they were put to death. RESULTS: Refluxed gastroduodenal juice, in the absence of MNAN, induced esophageal inflammatory changes (diffuse papillomatosis and hyperkeratosis) in 38 of 39 rats (97%), specialized columnar metaplasia (Barrett's esophagus) in four of 39 (10%), dysplasia in three of 39 (8%), and squamous cell carcinoma in one of 39 (3%). Diet did not influence the incidence of neoplasia in the absence of MNAN treatment. In rats treated with MNAN, refluxed gastroduodenal juice induced inflammation in 110 of 111 rats (99%), columnar metaplasia in 14 of 111 (13%), and cancer in 63 of 111 (57%). Fifty-eight percent of esophageal tumors were squamous cell carcinoma and 42% were adenocarcinoma. The highest incidence of tumors was observed in rats fed the semipurified high-fat diet (24 of 29; 83%) compared with rats fed the semipurified control diet (13 of 29; 45%), semipurified, calorie-restricted diet (15 of 27; 55%), and chow diet (11 of 26; 42%), p < 0.05. CONCLUSIONS: Reflux of gastroduodenal content into the lower esophagus of rats can induce both Barrett's metaplasia and neoplasia. Addition of a carcinogen increases the tumor yield and results in a proportion of the lesions being adenocarcinoma. This carcinogenic process is promoted by a diet with a high fat content.

Adenocarcinoma↗
PubMed1992

Metabolism of N-nitrosomethyl-n-amylamine by microsomes from human and rat esophagus.

Asymmetric dialkylnitrosamines induce esophageal cancer in rats and hence might be involved in the etiology of this cancer in humans. As a test of this hypothesis, we examined whether nitrosamines can be activated by segments of human esophagus and by microsomes of human and rat esophagus and liver. Specimens of 8 human esophagi were removed less than 6 h after death, and segments were incubated for 6 h with 23 and 300 microM N-nitrosomethyl-n-amylamine (NMAA). Hydroxy-NMAA yields were determined by gas chromatography-thermal energy analysis and were insignificant except for those of 5-hydroxy-NMAA, which were low. Microsomes were prepared from 4 batches of human esophagi and samples with 0.6 mg protein were incubated for 20 min with NMAA and cytochrome P-450 cofactors. We determined hydroxy-NMAAs as before and aldehydes by high-performance liquid chromatography of their 2,4-dinitrophenylhydrazones. Incubation of these microsomes with 12 mM NMAA yielded mean values of 0.64 nmol formaldehyde ("demethylation"), 0.21 nmol pentaldehyde ("depentylation"), and 0.56 nmol total hydroxy-NMAAs/min/mg protein. Metabolite yields under various conditions were determined, including a demonstration that carbon monoxide inhibited 81% of NMAA demethylation, indicating that cytochrome P-450 enzymes were involved. We also examined N-nitrosodimethylamine (NDMA) demethylation by the same microsomes. Rat esophageal microsomes dealkylated NMAA and NDMA similarly to human esophageal microsomes, but with 2-6 times and twice the activity, respectively. Human and rat esophageal microsomes demethylated 6 mM NMAA 18-20 times as rapidly as they demethylated 5 mM NDMA, in contrast to liver microsomes of these species, which demethylated 6 mM NMAA only 0.9-1.4 times as rapidly as they demethylated 5 mM NDMA. However, liver microsomes of both species were more active than esophageal microsomes for NMAA depentylation. The occurrence of NMAA demethylation and (to a lesser extent) depentylation with both human and rat esophageal microsomes is important because these are the activating reactions, and suggests that both human and rat esophagus contain P-450 isozymes that specifically dealkylate asymmetric dialkylnitrosamines.

Animals↗
PubMed1992

Duodenoesophageal reflux and the development of esophageal adenocarcinoma in rats.

BACKGROUND: The carcinogenic effect of duodenoesophageal reflux, gastroesophageal reflux, and nitrosamines was studied in the rat esophagus. METHODS: Twenty male Sprague-Dawley rats underwent esophagogastroplasty to produce gastroesophageal reflux and 60 underwent duodenoesophageal anastomosis to produce duodenoesophageal reflux. Forty-three animals underwent no operation and acted as controls. Carcinogens known to produce squamous tumors in the rat esophagus (2,6-dimethylnitrosomorpholine [DMNM] or methyl-n-amylnitrosamine [MNAN]) were tested in each group. RESULTS: The rate of squamous carcinoma was 25% for rats with DMNM alone, 30% for rats with MNAN alone, and 20% for rats with induced gastroesophageal reflux plus DMNM. The rate of malignant change rose to 80% in rats with induced duodenoesophageal reflux and DMNM and 67% with duodenoesophageal reflux and MNAN. With duodenoesophageal reflux, 50% of tumors were adenocarcinoma, in contrast to 100% squamous differentiation of tumors in rats given the carcinogens with esophagogastroplasty or no operation. CONCLUSION: The presence of duodenoesophageal reflux increased the frequency and changed the histologic type of esophageal cancer in nitrosamine-treated rats. This indicates that duodenoesophageal reflux plays a role in the development of esophageal adenocarcinoma.

Adenocarcinoma↗
PubMed1991

Positional specificity for methyl-n-amylnitrosamine hydroxylation by cytochrome P-450 isozymes determined with monoclonal antibodies.

Inhibitory monoclonal antibodies (MAbs) were used to determine the contribution of epitope-specific cytochrome P-450 isozymes in rat liver microsomes to hydroxylation of the esophageal carcinogen methyl-n-amylnitrosamine. These P-450-catalyzed reactions form 2-, 3-, 4-, and 5-hydroxymethyl-n-amylnitrosamine, formaldehyde (demethylation), and pentaldehyde (depentylation). With uninduced microsomes from male rats, MAb 1-68-11 inhibited 4-hydroxylation by 73% and demethylation by 46%. This indicated the major contribution of constitutive male-specific P-450 IIC11 to the metabolism. Inhibition studies with MAbs 2-66-3 and 1-91-3 indicated that P-450 IIB1 contributed 19% and IIE1 35% to demethylation. With uninduced microsomes from females, MAb 1-68-11 produced similar inhibitions to those in male rats, indicating that female-specific P-450 IIC12 (which is closely related to IIC11) also catalyzed 4-hydroxylation and demethylation. With microsomes from 3-methylcholanthrene-induced male rats, P-450 IA1 and/or IA2 were responsible for 60% of 3-hydroxylation and 40% of depentylation. With microsomes from phenobarbital-treated rats, P-450 IIB1 and IIB2 catalyzed all 6 reactions but especially 4-hydroxylation and depentylation, which were 50-75% inhibited by MAb 2-66-3. Microsomes from Aroclor-induced males behaved as if they were induced by both 3-methylcholanthrene and phenobarbital. After treatment with isoniazid (a P-450 IIE1 inducer), inhibition by MAb 1-91-3 indicated a 45% contribution of P-450 IIE1 to demethylation, and both P-450 IIE1 and IIB1 (or IIB2) appear to have been induced. A major finding with uninduced microsomes was the high specificity of MAb 1-68-11 for inhibiting 4-hydroxylation, indicating that P-450 IIC11 and IIC12 catalyzed most of this omega-1-hydroxylation. In microsomes from induced rats, the MAb inhibitions showed the role of the induced P-450 IA1 (or IA2), IIB1 (or IIB2), and IIE1 in methyl-n-amylnitrosamine hydroxylation at different positions, as well as the presence of P-450 IIC11. This study illustrates the usefulness of inhibitory MAbs for defining the contribution of individual P-450s to position-specific metabolism.

Animals↗
PubMed1991

Effects of 2,4,5-trichlorophenoxyacetic acid, pentachlorophenol, methylprednisolone, and Freund's adjuvant on 2-hydroxyethylnitrosourea carcinogenesis in MRC-Wistar rats.

A link was proposed between human non-Hodgkin's lymphoma and exposure to 2,4,5-trichlorophenoxyacetic acid (245T) and pentachlorophenol (PCP). To test this view and the hypothesis that immune suppression or stimulation could affect B-cell lymphoma (BCL) induction, we administered chronically to MRC-Wistar (MRC-W) rats of both sexes 98% pure 245T (600 mg/kg diet), 86% pure PCP (500 mg/kg diet), methylprednisolone (20 mg/kg ip weekly), and Freund's adjuvant (0.5 ml im every 3-6 wk) for 40 wk, together with 75 mg 2-hydroxyethylnitrosourea (HENU)/l drinking water, a system known to induce B-cell lymphoma. The 245T was shown to contain only 1-4 micrograms/kg each of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF), but the PCP contained 25 micrograms TCDD and 670 micrograms TCDF/kg. HENU given alone induced B-cell lymphoma and osteosarcoma as before, with higher incidences of both tumors in males than in females. The B-cell lymphoma diagnosis was confirmed by immunologic typing of cell-surface markers and by probes for gene rearrangements. Coadministration with HENU of three of the four test agents did not affect tumor incidence, but PCP acted synergistically with HENU to induce acute myelocytic leukemia. PCP given alone or with HENU induced a 40-67% incidence of liver cell adenomas in the female rats. These effects were probably not due to TCDD in the PCP. HENU induced acute myelocytic leukemia and lung tumors in Wistar rats and n-butylnitrosourea induced acute myelocytic leukemia in MRC-Wistar rats, indicating that B-cell lymphoma induction was specific to the HENU-MRC-Wistar rat model.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1991

Use of monoclonal antibodies to identify cytochrome P450 isozymes in rat liver microsomes that hydroxylate N-nitrosomethylamylamine at each of six positions.

Inhibition of enzyme activity by monoclonal antibodies (MAbs) was used to indicate which cytochrome P450 isozymes in Sprague-Dawley rat liver microsomes catalyse hydroxylation of the oesophageal carcinogen N-nitrosomethyl-n-amylamine (NMAA) to give 2- to 5-hydroxy-NMAA (HO-NMAA), formaldehyde and pentaldehyde. Liver microsomes (0.3-0.6 mg protein) were incubated (15 min, 23 degrees C) with 0.4 mg MAb and, after adding NMAA to 6 mM, incubated for 20 min at 37 degrees C. Mixtures were analysed for HO-NMAAs by gas chromatography-thermal energy analysis and for aldehydes by high-performance liquid chromatography of their 2,4-dinitrophenylhydrazones. The percentage inhibition by each MAb indicates the percentage metabolism by the corresponding P450 isozyme(s). These results indicate that the MAb to P450 IIB1 cross-reacts with P450 IIE1 and that the MAb to male-specific constitutive IIC11 cross-reacts with female-specific IIC12. Taking this into account, the main results were as follows. With uninduced male microsomes, 4-hydroxylation was catalysed mainly by IIC11 and demethylation by IIC11 and IIE1. With uninduced female microsomes, P450s reacting with the MAb to IIC11 (probably mainly IIC12) were responsible for most of the 4-hydroxylation and demethylation. With 3-methylcholanthrene-induced male microsomes, most 3-hydroxylation and some depentylation were due to IA1 or IA2. With phenobarbital-induced microsomes, all six reactions, but especially 4-hydroxylation and depentylation, were largely due to IIB1. With Aroclor-induced microsomes, all six reactions were catalysed by IIB1 and IA1 or IA2. The role of P450 IIC11 in 4-(omega-1)-hydroxylation was striking.

Animals↗
PubMed1990

2-Hydroxyethylnitrosourea induction of B cell lymphoma in female Swiss mice.

Groups of 30 adult Swiss mice of both sexes from the Eppley Institute breeding colony were treated with 37.5 or 75 mg 2-hydroxyethylnitrosourea (HENU)/l citrate buffer, given as drinking water on 4 days/week from 6-8 weeks of age for life. A third group of mice was untreated. Incidences of generalized B cell lymphoma (BCL) were 67% (males) and 87% (females) for the higher dose of the nitrosourea, 29% (males) and 79% (females) for the lower dose and 0% (males) and 7% (females) for the untreated mice. Tumor latencies were 23 weeks (high dose) and 27 weeks (low dose) in the females and 6-7 weeks longer in the males. A B-cell origin of the lymphomas was indicated by the pathology and tumor distribution and was confirmed in 4 mice by immunophenotyping and in 6 mice by probes for gene rearrangements. This system may be an effective means of inducing B cell lymphoma with a carcinogen.

Animals↗
PubMed1989

Formation of hydroxy derivatives, aldehydes, and nitrite from N-nitrosomethyl-n-amylamine by rat liver microsomes and by purified cytochrome P-450 IIB1.

The metabolism was examined of the esophageal carcinogen N-nitrosomethylamylamine (NMAA) by liver microsomes and slices from adult male Sprague-Dawley rats. Hydroxylation at C-2 to C-5 of the amyl group to give stable hydroxy-NMAAs was studied by gas chromatography-thermal energy analysis to determine the products. Microsomal metabolism produced mainly 4-hydroxy-NMAA, proceeded optimally in 100 mM phosphate at pH 7.4, and showed no sex differences. Induction by phenobarbital (PB) and 3-methylcholanthrene produced effects which were similar in slices and microsomes, with PB inducing hydroxylation at all positions and 3-methylcholanthrene specifically inducing 3-hydroxylation by factors of 2- and 6-fold. Clofibrate and isoniazid treatments did not affect NMAA metabolism by liver slices. Aroclor-1254 strongly induced microsomal 2- and 3-hydroxylation. For 2- to 5-hydroxylation, Km values for uninduced microsomes were, respectively, 1.6, 1.2, 0.3, and 1.1 mM, with Vmax of 0.08, 0.26, 1.06, and 0.15 nmol/min/mg protein. With PB-induced microsomes, all 4 Km values were 0.4-0.7 mM. Liver microsomal production of nitrite and aldehydes from NMAA was determined colormetrically or (for pentaldehyde) by high-pressure liquid chromatography of the 2,4-dinitrophenylhydrazone. Uninduced microsomes produced nitrite, formaldehyde and pentaldehyde from 0.6 mM NMAA at rates that were, respectively, 0.15, 0.72, and 1.15 times that for 4-hydroxylation. PB especially induced depentylation, whereas 3-methylcholanthrene induced depentylation and denitrosation, but suppressed demethylation. A reconstituted system containing cytochrome P-450 IIB1 gave metabolite ratios similar to those in PB-induced microsomes. The results account for most of the possible primary metabolites of NMAA and demonstrate the selectivity for metabolism at each position.

Aldehydes↗
PubMed1989

Ketonitrosamines as metabolites of methyl-n-amylnitrosamine (MNAN) and its hydroxy derivatives in the rat.

In a previous study of the metabolism of methyl-n-amylnitrosamine (MNAN) in the rat, 2- to 5-hydroxy-MNAN (HO-MNAN) were provisionally identified as metabolites and the identity of 4-HO-MNAN was confirmed by mass spectrometry. We now describe syntheses and mass and other spectra for 2- to 5-oxo-MNAN. Two previously unidentified MNAN metabolites were shown to be 3- and 4-oxo-MNAN. In addition to 4-HO-MNAN, we confirmed 3-HO-, 4-oxo- and (less certainly) 2-HO-MNAN as urinary MNAN metabolites by GLC-MS of HPLC fractions. Analysis with and without beta-glucuronidase treatment showed that the urinary HO-MNANs occurred as their beta-glucuronides. MNAN (25 mg/kg injected i.p.) had a blood half-life of 21 min in adult male rats. The blood also contained 4-HO- and 4-oxo-MNAN, which showed maximum levels that were 13 and 26% respectively of that for MNAN, and were cleared more slowly than MNAN. On incubation for 3 h with MNAN, rat esophagus produced 3- and 4-oxo-MNAN in yields that were 5% of those for the corresponding HO-MNANs. For MNAN metabolism, the 4-oxo-/4-HO-MNAN ratio of metabolites was 5% for adult rat liver and was 22% for adult hamster liver and 9-day-old rat liver. On incubation with 4-HO-MNAN for 3 h, oxidation to 4-oxo-MNAN was 16-25% for adult hamster or 9-day-old rat liver slices and for adult hamster liver homogenate. Homogenate activity was concentrated in the microsomal fraction, for which NAD was a more effective co-factor than NADP. A bacterial alcohol dehydrogenase oxidized 4-HO- to 4-oxo-MNAN in 38% yield/3 h. None of these preparations oxidized 2-HO- to 2-oxo-MNAN. It was concluded that 3- and 4-oxo-MNAN were metabolites of MNAN, apparently (for 4-oxo-MNAN) via HO-MNAN oxidation by a microsomal NAD-dependent enzyme, that 4-HO- and 4-oxo-MNAN formation was a major route of MNAN metabolism, and that 4-oxo-MNAN might play a role in MNAN carcinogenesis.

Animals↗
PubMed1988

Hydroxy metabolites of methyl-n-amylnitrosamine produced by esophagus, stomach, liver, and other tissues of the neonatal to adult rat and hamster.

We measured the ability of neonatal to adult MRC-Wistar rat and Syrian hamster tissues to convert the esophageal carcinogen methyl-n-amylnitrosamine (MNAN) into the stable metabolites 2- to 5-hydroxy-MNAN and 3- and 4-oxo-MNAN. Slices or pieces of freshly removed tissues were incubated for 3 h with 23 microM MNAN and dichloromethane extracts were analyzed by gas chromatography-thermal energy analysis. The sum of the metabolites was expressed as percent metabolism of MNAN/100 mg tissue ("percent metabolism"). Tissues of animals from 1 day before birth to 56-70 days of age were examined. Metabolites in rat esophagus reached 12.6% at 6 days of age, three times the adult level, and that in hamster esophagus reached 13.1% at birth, 22 times the adult level. Forestomach metabolism was 1.9% in 3-day rats and 5.7% in 3-day hamsters, though the adult levels were less than 0.5%. Metabolism in rat, but not hamster, liver showed a peak at 9 days that was 3.6 times the adult level. Hamster, but not rat, skin showed about 1% metabolism. Total metabolism by glandular stomach, lung, and trachea of both species also showed changes with age. Ratios between 2-, 3-, 4-, and 5-hydroxy-MNAN were of three types: considerable 2-, 3-, and 4-hydroxy-MNAN, typical of esophagus; mainly 4-hydroxy-MNAN, typical of liver; and mainly 5- with some 4-hydroxy-MNAN, typical of rat lung. Incubation of adult rat liver and esophagus with varied MNAN concentrations showed apparent Km values of 150 (esophagus) and 300 (liver) microM. Metabolite yields after young and adult rat esophagus and liver were incubated with 23 microM MNAN for 1, 2, or 3 h indicated that differing in vitro stability of enzyme activities did not explain the age differences. The 2.9- to 3.6-fold differences in total metabolite yield between young and adult rat esophagus and liver, observed when these tissues were incubated with 23 microM MNAN, was in contrast to the 1.3- to 1.6-fold difference when these tissues were incubated with 300 or 600 microM MNAN, suggesting that much of the observed age difference was specific to low MNAN concentrations. MNAN hydroxylation could be used to indicate tissue susceptibility to MNAN carcinogenesis and the presence of enzymes (probably cytochrome P-450 isozymes) that catalyze each of the three types of MNAN metabolism.

Animals↗
PubMed1988

Induction of hyperplastic liver nodules in Wistar and MRC-Wistar rats by phenobarbital and the liver carcinogens acetoxime, 1-nitroso-5,6-dihydrouracil and 3-nitroso-2-oxazolidinone.

We tested the ability of phenobarbital and two liver carcinogens, acetoxime and 1-nitroso-5,6-dihydrouracil (NDHU), to induce hyperplastic liver nodules (HLN) in MRC-Wistar and Wistar rats, using a system that included a single diethylnitrosamine (DEN) treatment, partial hepatectomy, and administration of the test compound in drinking water for 8 weeks. All three compounds induced significant HLN frequencies (number of HLN/cm2) in both rat strains. When the results for each strain were "normalized" for each compound and then combined, HLN frequency in MRC-Wistar rats was significantly lower (P less than 0.01) than that in Wistar rats. The weak liver carcinogen 3-nitroso-2-oxazolidinone (NOZ) did not induce a significant HLN frequency in MRC-Wistar rats. Acetoxime was highly volatile and was not mutagenic in the Ames test under a variety of conditions. The results for acetoxime are of interest because simple oximes are common constituents of oil paints. HLN induction by nitrosodihydrouracil is of interest because, unlike most liver carcinogens, this compound probably does not require metabolic activation and shows only a mild acute hepatoxicity.

Animals↗
PubMed1988

Nitrosamine formation from amines applied to the skin of mice after and before exposure to nitrogen dioxide.

Skin lipids of mice exposed to NO2 contain lipid-soluble nitrosating agent(s) (NSA) that react in vitro with amines to produce nitrosamines. To test whether this reaction occurs in skin, we exposed mice to 50 ppm NO2 for 4 h and, 20 h later, applied 25 mg morpholine or N-methylaniline to the skin, which was then analyzed for the corresponding nitrosamine. When morpholine was applied, mean N-nitrosomorpholine yield was only 0.3 nmol/mouse (not significant). When N-methylaniline was applied and mice were killed after 10-40 min, N-nitroso-N-methylaniline yield in the skin was 13-21 nmol/mouse of which 87% occurred in the hair. NSA formation when mice were exposed to 6.5 ppm NO2 was only 0.15% of that for exposure to 50 ppm NO2. NSA occurred mostly in surface lipids of the skin and its in vitro reaction to give nitrosamines was not inhibited by alpha-tocopherol. When morpholine was painted and mice were then exposed to 55 ppm NO2 for 30 min, the skins contained 19 nmol N-nitrosomorpholine/mouse, attributed to a direct reaction between NO2 and the amine. We concluded that nitrosamine formation in skin by this direct reaction may be more important than the reaction of amines with NO2-derived NSA.

Aniline Compounds↗
PubMed1987

Alpha-acetoxy derivatives of methyl-2-oxopropylnitrosamine: synthesis, hydrolysis rate and bacterial mutagenicity.

N-Methyl-N-2-oxopropylnitrosamine (MOP) induces pancreatic tumors in hamsters. As models for the putative proximate carcinogenic alpha-hydroxy derivatives, we studied N-acetoxymethyl-N-2-oxopropylnitrosamine (AMOP) and N-methyl-N-(1-acetoxy-2-oxopropyl)nitrosamine (MAOP). AMOP was synthesized from aminoacetone by the method of Roller et al. [1975), Tetrahedron Lett., 25, 2065-2068) and MAOP was synthesized by acetoxylation of MOP with lead tetraacetate. The half-lives of AMOP, MAOP and acetoxymethylmethylnitrosamine (ADMN) in aqueous buffer decreased as the pH rose from 5 to 9, with values at pH 5 of 2.8 X 10(4) min for AMOP, 3.2 X 10(3) min for ADMN, and 23 min for MAOP. Mutagenicity was examined in Salmonella typhimurium TA1535, using a pre-incubation at pH 5 without microsomal activation. The mutagenic potency, expressed as revertants/mumole, was 56 for AMOP, 150 for ADMN, and 4.5 X 10(4) for MAOP. Hence, hydrolysis rates at pH 5 were probably important in determining the relative mutagenicity.

Chemical Phenomena↗