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PubMed1987

Formation of hemoglobin adducts upon treatment of F344 rats with the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine.

[5-3H]4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNK), [C3H3]NNK, and [5-3H]N'-nitrosonornicotine ([5-3H]NNN) were administered to F344 rats by i.p. injection. Levels of tritium present per milligram globin, 24 h after treatment were 720 fmol (0.1% of dose) for [5-3H]NNK, 640 fmol for [C3H3]NNK, and 370 fmol for [5-3H]NNN. Tritium was detectable in globin 7-8 weeks after treatment with [5-3H]NNK or [5-3H]NNN. Approximately 10-15% of the bound tritium in the globin of rats treated with [5-3H]NNK was released upon incubation of the globin with dilute NaOH or HCl. The released material was identified as 4-hydroxy-1-(3-pyridyl)-1-butanone; it was detectable in globin for 6 weeks (t1/2 = 9.1 days) after administration of [5-3H]NNK. 4-Hydroxy-1-(3-pyridyl)-1-butanone was also formed upon NaOH treatment of globin isolated from rats injected with [5-3H]NNN or [5-3H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone. The formation of 4-hydroxy-1-(3-pyridyl)-1-butanone under these conditions is consistent with a mechanism by which 4-(3-pyridyl)-4-oxobutyldiazohydroxide is produced upon metabolic alpha-hydroxylation of NNK or NNN and binds to globin of hemoglobin, yielding an adduct which is readily hydrolyzed by acid or base. Support for this mechanism was obtained by in vitro experiments. Levels of 4-hydroxy-1-(3-pyridyl)-1-butanone released upon base treatment of globin were 50 times greater after incubation of rat hemoglobin with [5-3H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone than with either [5-3H]NNK or [5-3H]4-hydroxy-1-(3-pyridyl)-1-butanone. The results of this study suggest methods that might be applicable for assessing the molecular dosimetry of NNK and NNN in individuals exposed to tobacco and tobacco smoke.

Animals↗
PubMedDate not supplied

Microbial nitrosamine formation in palm wine: in vitro N-nitrosation by cell suspensions.

The ability of certain species of bacteria and yeasts that usually contaminate fresh palm sap to induce the formation of the carcinogen dimethylnitrosamine from suitable precursors (trimethylamine, dimethylamine, nitrate, and nitrite) was investigated in vitro under neutral and acid pH conditions. In the incubation media containing cell suspensions of each species of test organism, namely, Aerobacter, Micrococcus, Serratia, Saccharomyces, and two unidentified yeasts and the precursors, added in varying concentrations, the presence of dimethylnitrosamine was indicated. The possible role of indwelling microorganisms in the elaboration of the hazardous compound in fermenting palm wine is discussed.

Bacteria↗
PubMed1987

Molecular dosimetry of DNA adduct formation and cell toxicity in rat nasal mucosa following exposure to the tobacco specific nitrosamine 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and their relationship to induction of neoplasia.

The molecular dosimetry of O6-methylguanine (O6MG) formation in DNA and cytotoxicity in respiratory and olfactory mucosa was determined during administration of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to male Fischer 344 rats. The dose response for O6MG formation differed considerably between respiratory and olfactory mucosa. The dose response was nonlinear in respiratory mucosa where the slope of the curve was very large for doses of NNK ranging from 0.3 to 3.0 mg/kg but much smaller in the dose range of 10 to 100 mg/kg. In contract, the dose response in the olfactory mucosa did not demonstrate such a large change in slope over the same dose range. The concentration of O6MG formed to dose of NNK ratio, an index of efficiency of alkylation, increased dramatically only in the respiratory mucosa as the dose of NNK was decreased from 100 to 0.3 mg/kg. The concentration of O6MG was four times greater in respiratory than olfactory mucosa after treatment of rats with 1 mg/kg NNK. Alkylation in the two regions of the nose became similar as the dose of NNK was increased. In rats treated for up to 12 days with NNK (10 mg/kg/day), the concentration of O6MG was 60 to 90% greater in respiratory than olfactory mucosa throughout treatment. Regional differences in the amount of O6MG formed may stem from the presence of a low Km pathway for biotransformation of NNK in the cells of the respiratory mucosa. This conclusion is supported by autoradiographic studies. Four h after treatment with 1 mg/kg [3H]NNK, silver grains were more heavily concentrated in respiratory than olfactory epithelium. Histopathological examination of the nasal passages revealed dose related, cell specific differences in toxicity following treatment of rats with 10, 30, or 100 mg/kg NNK for 12 days. No toxicity was observed in the nose when 1 mg/kg NNK was administered. Bowman's glands underlying the olfactory mucosa and Steno's glands were the most sensitive sites for toxicity, exhibiting necrosis after as little as 2 days of treatment with 10 mg/kg NNK. Damage to these glands progressed in a dose- and time-dependent manner. Respiratory epithelium exhibited only mild toxicity while basal cell metaplasia was evident in olfactory epithelium. Rats treated with NNK for 20 weeks (50 mg/kg, three times a week) had a 45% incidence of carcinomas in the olfactory region. These neoplasms appeared to arise from Bowman's glands. In contrast, there was only a 5% incidence of malignant neoplasia and a 29% incidence of benign neoplasia in the respiratory region.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

The pig as an animal model for the study of nitrosamine metabolism.

Surgical procedures have been developed that permit the sampling of portal blood, bile and hepatic blood in intact pigs. Animals so prepared have been used to study liver metabolism and biliary excretion of N-nitrosodimethylamine (NDMA) following oral and intravenous dosing.

Animals↗
PubMed1987

Could N-nitrosamino phosphates be transport forms of activated N-nitrosamines?

The stability of N-nitroso-N-methylamine-N-ethyl phosphate (NMEP) and N-nitroso-N-ethylamine-N-ethyl phosphate (NEEP) was studied in rat serum and in rat liver homogenate and found to be sufficiently high for the phosphates to be transported in vivo. In liver homogenates, the cleavage was more efficient, and a higher phosphatase activity was found in liver microsomal and cytosolic fractions than in serum. The substances exert a distinct activity in the Salmonella typhimurium mutagenicity test.

Alkaline Phosphatase↗
PubMed1987

Biochemical events in nitrosamine-induced hepatocarcinogenesis: relevance of animal data to human carcinogenesis.

Administration of carcinogens to experimental animals results in the early formation of phenotypically altered cell foci. Evidence suggesting their intermediary role in hepatocarcinogenesis, and some of their biological properties are reviewed. Two concepts relating to the mechanism of tumour promotion are described briefly, i.e., the 'resistant cell' hypothesis and that of 'overexpression of adaptive growth'. It is concluded that studies on liver foci may be helpful in elucidating the nature of the events involved in the initiation of carcinogenesis. Some aspects relating to human hepatocarcinogenesis are also considered briefly.

Animals↗
PubMed1987

In-vitro production of nitrosamines by bacteria isolated from the operated stomach.

Evidence is presented of in-vitro catalysis of nitrosation by organisms isolated from the hypoacidic operated stomach. Subjects taking part in a prospective study of potential premalignancy after benign ulcer surgery underwent endoscopy, and samples of gastric juice were obtained aseptically. The organisms present were identified using the API system and tested for their ability to catalyse the nitrosation of the secondary amine, morpholine, at neutral pH and 37 degrees C. Four of the five species tested were found to be capable of the catalysis. Cellular disruption and denaturation of protein abolished the catalytic ability, suggesting that the catalysis is mediated by an enzymic system. Osmotic shock experiments indicate that the enzyme site may be on the inner membrane.

Female↗
PubMed1987

Investigations on the molecular dosimetry of tobacco-specific N-nitrosamines.

Approaches for assessing molecular dosimetry of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) in humans by measurement of haemoglobin or DNA adducts are discussed. NNK and NNN form haemoglobin adducts in Fischer 344 rats. Acid or base hydrolysis of the globin gives 4-hydroxy-1-(3-pyridyl)-1-butanone, which can be detected in rat blood up to six weeks after injection of NNK; it may be a useful marker for assessing uptake and metabolic activation of NNK and NNN in tobacco consumers. NNK and its major metabolite, 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAI), methylated DNA of rat liver, lung and nasal mucosa to similar extents. NNAI is formed in human tissues from NNK, but immunoassays for O6-methyldeoxyguanosine (O6-medGuo) in exfoliated oral cells from snuff-dippers have been negative. NNK is also expected to form pyridyloxobutyl adducts in DNA; 32P-postlabelling assays for these adducts are being developed and appear to hold promise for detecting NNK- or NNN-DNA adducts in vivo.

Animals↗
PubMedDate not supplied

Analysis of piperazine drug formulations for N-nitrosamines.

A quantitative method is described for the measurement of N-mononitrosopiperazine (NPIP) and N,N'-dinitrosopiperazine (DNPIP) in drug formulations containing piperazine, using a gas chromatograph interfaced to a thermal energy analyzer (GC/TEA). The method has detection limits of 20 ppb for NPIP and 12 ppb for DNPIP. In a survey of 6 products available on the Canadian market, all contained NPIP at levels of 0.38-15.3 micrograms NPIP/g piperazine and none contained any detectable amount of DNPIP.

Chromatography, Gas↗