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S S Hecht

Publications and source records attributed to S S Hecht.

At least 271 records · Page 15Linked to original sources
PubMed1983

Effects of alpha-deuterium substitution on the mutagenicity of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic tobacco specific nitrosamine, can be converted to electrophilic diazohydroxide intermediates by metabolic hydroxylation of either the methylene carbon (carbon 4) or the methyl carbon attached to the nitrosamine group. To investigate the relative importance of these two processes in NNK mutagenesis, we synthesized 4,4-dideutero-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone([4,4,-D2]NNK) and 4-(trideuteromethylnitrosamino)-1-(3-pyridyl)-1-butanone ([CD3] NNK), and evaluated their mutagenic activities in Salmonella typhimurium tester strains. In the presence of Aroclor induced rat liver 9000 g supernatant, NNK and [4,4-D2]NNK had comparable mutagenic activities towards S. typhimurium TA 1535 and TA 100, but [CD3]NNK was inactive in both strains. These results suggest that hydroxylation of the methyl group of NNK is more important than hydroxylation of carbon 4 in its activation to a mutagen. To test the inherent mutagenicity of 4-oxo-4-(3-pyridyl)butyldiazohydroxide and methyldiazohydroxide which would be formed by methyl hydroxylation or carbon 4 hydroxylation, respectively, we compared the mutagenicities, without activation, of the corresponding model compounds, 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone and carbethoxynitrosaminomethane (methylnitrosourethane). Both compounds were highly mutagenic toward S. typhimurium TA 1535 and TA 100, but at doses of 4 x 10(-3) to 4 x 10(-4) mumol/plate, only 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone was mutagenic. These results are consistent with those obtained with the deuterium substituted compounds and indicate the importance of 4-oxo-4-(3-pyridyl)butylation of DNA in NNK mutagenesis.

Deuterium↗
PubMed1983

5-Methylchrysene metabolism in mouse epidermis in vivo, diol epoxide--DNA adduct persistence, and diol epoxide reactivity with DNA as potential factors influencing the predominance of 5-methylchrysene-1,2-diol-3,4-epoxide--DNA adducts in mouse epidermis.

5-Methylchrysene (5-MeC) can form two bay region dihydrodiol epoxides: 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I) which has the methyl group and the epoxide ring in the same bay region, and 7,8-dihydroxy-9,10-epoxy-7,8,10-tetrahydro-5-methylchrysene (DE-II). In a previous study, we observed that the ratio of DE-I:DNA adducts to DE-II:DNA adducts in mouse epidermis, 24 h after application of [3H]5-MeC metabolites was 2.7 to 1. To investigate the basis for this observation we have now studies: (i) the formation of [3H]5-MeC in mouse epidermis in vivo at various time intervals from 0.33 to 24 h; (ii) the persistence of DE-I:DNA adducts and DE-II:DNA adducts in mouse epidermis at 4-48 h after application of [3H]5-MeC; and (iii) the reactions of DE-I and DE-II with calf thymus DNA in vitro. In contrast to results obtained with mouse liver 9000 grams supernatant, the dihydrodiol precursors of DE-I and DE-II were present in equivalent quantities in mouse epidermis in vivo at every time point studied. The ratio of DE-I:DNA adducts to DE-II:DNA adducts in mouse epidermis was constant throughout the time period studied. However, the extent of formation of DE-I:DNA adducts was greater than that of DE-II:DNA adducts upon reaction of DE-I or DE-II with calf thymus DNA in vitro. These results suggest that differences in reactivity with DNA of DE-I and DE-II may bw responsible for the higher levels in mouse epidermis of DE-I:DNA adducts compared with DE-II:DNA adducts and provide a possible basis for the observed enhancing effect of a bay region methyl group on the carcinogenicity of polynuclear aromatic hydrocarbons.

Animals↗
PubMed1983

Tumor promoters and cocarcinogens in tobacco carcinogenesis.

Cigarette smoke induces carcinoma of the larynx in Syrian golden hamsters and is active as a tumor promoter in hamsters pretreated with a low dose of a PAH, nitrosamine, or nitrosamide. These tumorigenic effects are only observed with total smoke, but not with the gas phase alone. This demonstrates that the tumorigenic agents reside primarily in the particulate phase. According to fractionation experiments, a number of four- and five-ring aromatic hydrocarbons serve as the major tumor initiators in tobacco smoke. Tumor promoters reside primarily in weakly polaric neutral subfractions and in the weakly acidic portion of the particulate matter and include certain unsaturated hydrocarbons and phenolic compounds. Cocarcinogenic activity is a characteristic feature of tobacco smoke and its particulates. Among the cocarcinogens formed during combustion are catechols and certain nontumorigenic aromatic hydrocarbons and terpenes. Nicotine may also serve as a cocarcinogen as is indicated by preliminary data. The action of tumor promoters and cocarcinogens in tobacco carcinogenesis, the precursors for tobacco smoke promoters and cocarcinogens, and methods for their reduction in smoke are discussed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1983

Identification and mutagenicity of metabolites of 1-nitropyrene formed by rat liver.

The metabolism of 1-nitropyrene by rat liver 9000 X g supernatant was investigated. Under aerobic conditions, ring oxidation to 1-nitropyren-3-ol, 1-nitropyren-6-ol, 1-nitropyren-8-ol, and 4,5-dihydro-4,5-dihydroxy-1-nitropyrene and nitroreduction to 1-aminopyrene were observed. Metabolites were identified by their ultraviolet, mass, and nuclear magnetic resonance spectra; by chemical transformations; and by comparison to reference standards. When incubations were carried out in an atmosphere of 4% O2 in N2, 1-aminopyrene was the major metabolite. The mutagenic activities of 1-nitropyren-3-ol, 1-nitropyren-6-ol, and 1-nitrosopyrene were assessed in Salmonella typhimurium strains TA 98 and TA 100. In strain TA 98, without activation, doses of 0.5 micrograms/plate or less of these three compounds were more mutagenic than was 1-nitropyrene; however, their activities decreased rapidly at higher doses. In the presence of rat liver 9000 X g supernatant, they were less mutagenic than was 1-nitropyrene at all doses tested. In S. typhimurium TA 100, without activation, 1-nitropyren-3-ol, 1-nitropyren-6-ol, and 1-nitrosopyrene were more mutagenic than was 1-nitropyrene at doses of 0.25 micrograms/plate or less, but their activities decreased at higher doses. In strain TA 100, with activation, only 1-nitropyren-6-ol was more mutagenic than was 1-nitropyrene. The results of this study indicate that both nitroreduction and ring oxidation may be involved in the mutagenic activity of 1-nitropyrene.

Animals↗
PubMed1983

Tissue distribution of the tobacco-specific carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and its metabolites in F344 rats.

The tissue distribution of the tobacco-specific N-nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the F344 rat was studied by whole-body autoradiography and high-performance liquid chromatography. The results of the wholebody autoradiography experiments indicate that the substance is able to freely cross biological membranes and reach all tissues of the body. A high level of tissue-bound metabolites occurred in the mucosa of the ethmoturbinates, in the lung, and the liver, which are the targets for the carcinogenicity of NNK in F344 rats. However, tissue-bound radioactivity was also present in non-target tissues such as the lateral nasal gland(Steno's gland), the tracheal mucosa, and the mucosa of the nasopharyngeal duct. A high level of unbound radioactivity occurred in the preputial gland, submaxillary and adrenal glands, and the urinary and gastrointestinal systems. High localization of unbound radioactivity was observed in the stomach lumen not only after p.o. but also after i.v. administration of NNK. Analysis of extracts of the stomach contents by high-performance liquid chromatography indicated that, due to their basicity, NNK and its metabolites were trapped in the gastric juice and later reabsorbed from the intestinal tract. Analysis of unbound metabolites in various tissues and in the urine after i.v. or p.o. administration of [carbonyl-14C]NNK indicated metabolism and excretion of products resulting from alpha-carbon hydroxylation, carbonyl reduction, and pyridine N-oxidation of NNK. After p.o. administration of [14CH3]NNK, 47% of the dose was recovered as 14CO2. [carbonyl-14C]NNK, however, was not metabolized to 14CO2. Levels of in vitro metabolism of [14CH3]-NNK to 14CO2 or incorporation of radioactivity into the acid-insoluble material after incubation with [carbonyl-14C]NNK were the highest in the nasal mucosa. Thus, the high activity of NNK-activating enzymes present in the nasal cavity is apparently an important factor in the etiology of NNK-induced neuroepitheliomas. In vitro autoradiography experiments showed that NNK is metabolized in the mucosa of the ethmoturbinates, the lung, and the liver, suggesting that the tumors are induced by metabolites formed locally in the target tissues. In the lung, the labeling was higher in the bronchial tree than in the lung parenchyma.

Animals↗
PubMed1983

Effects of route of administration and dose on the carcinogenicity of N-nitrosodiethanolamine in the Syrian golden hamster.

N-Nitrosodiethanolamine was assayed for carcinogenicity in Syrian golden hamsters by s.c. injection, topical application, and oral cavity swabbing. Three groups of 30 hamsters each received 27 weekly s.c. injections of either 500, 170, or 58 mg of N-nitrosodiethanolamine per kg in 0.9% NaCl solution. In the group treated with 500 mg/kg, 19 of 30 animals developed nasal cavity tumors, 7 of 30 had tracheal tumors, and 2 of 30 had tumors of the larynx. Among the animals treated with 170 mg/kg, 7 of 29 presented with nasal cavity tumors and 4 of 29 presented with tracheal tumors. In the group treated with 58 mg/kg, only two tracheal tumors were observed. Acetone solutions of N-nitrosodiethanolamine were applied to the shaved backs of three groups of 30 hamsters, each three times weekly for 36 weeks, at doses of 25, 8, or 2.5 mg; the total doses were the same as in the groups treated by s.c. injection. At the 25-mg dose level, 5 of 30 animals developed nasal cavity tumors and 4 of 30 animals had tumors of the trachea. No skin tumors were observed. The incidence of respiratory tract tumors in the groups treated with 8 or 2.5 mg was not significant compared to controls. The oral cavities of 40 hamsters were swabbed three times weekly for 45 weeks with 20 mg of N-nitrosodiethanolamine; the total dose was the same as the highest doses given by s.c. or topical administration. Seventeen of 38 hamsters had nasal cavity tumors, 6 of 38 developed tracheal tumors, and 1 of 38 presented with a tumor of the larynx. No tumors were observed in the oral cavity. The results of this study demonstrate that N-nitrosodiethanolamine is organospecific for the Syrian golden hamster nasal cavity and trachea and that it induces tumors in these sites at doses lower than previously reported.

Administration, Oral↗
PubMed1983

Metabolism of tobacco-specific nitrosamines by cultured rat nasal mucosa.

The metabolism of two nasal carcinogens, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was investigated using cultured nasal septa of F344 rats. The explants were cultured with 14C-labeled N-nitrosamines, and unbound metabolites present in the medium were quantitated by high-performance liquid chromatography. The results indicated that the mucosa of the nasal septum had a marked capacity to metabolize NNN and NNK to hydroxylated products which were released into the culture media. Extensive activation by alpha-carbon hydroxylation of NNN (preferentially 2'-carbon hydroxylation) and NNK was observed, whereas no deactivation by pyridine N-oxidation could be detected. Microautoradiographic studies of explants showed that binding of radioactivity occurred preferentially in the respiratory and olfactory epithelia and in the subepithelial glands of the nasal mucosa. The results suggest that reactive metabolites of NNN and NNK are formed within the target tissue rather than being transported from the liver to the nasal mucosa. The results also show that the culture of nasal septa can be used to ascertain the role of the nasal mucosa in the activation of nasal-specific carcinogens.

Animals↗
PubMed1982

Comparison of microsomal inducer pretreatment on the in vitro alpha-hydroxylation and mutagenicity of N-Nitrosopyrrolidine in rat and hamster liver.

The effect of modifiers of liver mixed function oxidase activity on the in vitro alpha-hydroxylation and mutagenicity of N-nitrosopyrrolidine (NPYR) has been examined in rats and hamsters. Hamster post-mitochondrial supernatants were able to convert NPYR to a mutagen more efficiently than rat preparations under all conditions studied. Aroclor 1254 pretreatment caused the greatest increase in mutagenic activity in both species while phenobarbital and 3-methylcholanthrene pretreatment gave intermediate values when compared to uninduced preparations. Microsomal alpha-hydroxylation of NPYR was induced by Aroclor 1254 pretreatment in both species. Pretreatment with 3-methylcholanthrene increased alpha-hydroxylation in hamsters but decreased it in rats. Phenobarbital pretreatment only slightly increased microsomal alpha-hydroxylation in either species. When microsomal alpha-hydroxylation rates were expressed per gram wet weight of liver, better agreement between rates of alpha-hydroxylation and mutagenicity in phenobarbital pretreated animals was obtained since inducer associated changes in total microsomal protein content were taken into account. An example of differential induction of an activation pathway (alpha-hydroxylation) and a degradative pathway (aldehyde dehydrogenase) is presented to illustrate a potential source of error in the interpretation of metabolic data obtained from post-microsomal supernatants and whole animal studies.

Animals↗
PubMed1982

Comparative tumor initiating activity on mouse skin of 6-nitrobenzo[a]pyrene, 6-nitrochrysene, 3-nitroperylene, 1-nitropyrene and their parent hydrocarbons.

6-Nitrobenzo[a]pyrene, 6-nitrochrysene, 3-nitroperylene, 1-nitropyrene, and the corresponding parent hydrocarbons were tested for tumor initiating activity on mouse skin with promotion by tetradecanoylphorbol acetate. The initiating doses of 6-nitrobenzo[a]pyrene and benzo[a]pyrene were 0.05 mg each; for all other compounds the initiating doses were 1.0 mg. 6-Nitrochrysene induced tumors in 60% of the mice (2.1 tumors per mouse), but was significantly less tumorigenic than chrysene. 3-Nitroperylene induced tumors in 42% of the mice (0.5 tumors per mouse) and was significantly more active than perylene. Neither 1-nitropyrene nor 6-nitrobenzo[a]pyrene exhibited significant tumorigenic activity in the concentrations tested.

Animals↗
PubMed1982

N-Nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine in household dishwashing liquids.

Eleven household dishwashing liquids and four household surface cleaners were analysed for N-nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine by gas chromatography with detection using a Thermal Energy Analyzer. Both nitrosamines were found in three of the dishwashing detergents and one of the surface cleaners. [1-14C]-N-Nitroso-N-methyldodecylamine was used to determine recoveries, which were between 65 and 88%. Levels of N-nitroso-N-methyldodecylamine ranged from 112 to 661 ppb and those of N-nitroso-N-methyltetradecylamine from 46 to 151 ppb. A simple method was developed to screen the products for N,N-dimethyldodecylamine-N-oxide, a surfactant ingredient suspected of being the source of these nitrosamines. By application of this method it was established that all of the products formulated with this amine oxide contained these two nitrosamines, whereas in products that did not contain this ingredient, these nitrosamines were not detected.

Chromatography, Gas↗
PubMed1982

Quantitative analysis of catechol and 4-methylcatechol in human urine.

A method was developed for the quantitative analysis of catechol and 4-methylcatechol in human urine. [U-14C]Catechol was used as in internal standard. Urine was treated with beta-glucuronidase and sulphatase, acidified and extracted with ether. The ether extract was silylated and analysed by glass capillary gas chromatography. Catechol and 4-methylcatechol occurred in urine primarily as conjugates. Levels of catechol and 4-methylcatechol in the urine of nonsmokers on unrestricted diets were 10 +/- 7.3 (mean +/- 1 SD) and 3.4 +/- 2.3 mg/24 hr, respectively. Nonsmokers on uniform restricted diets, in which the intake of plant-derived products was limited, excreted 4.4 +/- 1.2 mg catechol and 8.1 +/- 1.7 mg 4-methylcatechol/24 hr. Smokers on the same restricted diet excreted 6.8 +/- 3.0 mg catechol and 6.1 +/- 2.6 mg 4-methylcatechol/24 hr. These results indicate that diet is a major factor in determining urinary catechol levels and that the contribution of smoking is comparatively small. Catechol and 4-methylcatechol appear to have different dietary precursors.

Adult↗