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Biomedical subjects

S S Hecht

Publications and source records attributed to S S Hecht.

At least 307 records · Page 17Linked to original sources
PubMed1981

A study of tobacco carcinogenesis. XX. Role of catechol as a major cocarcinogen in the weakly acidic fraction of smoke condensate.

The weakly acidic fraction of cigarette smoke condensate was fractionated by preparative high-pressure liquid chromatography into major subfractions I-IV. Major subfractions II and III were fractionated further into subfractions A-J. Subfractions A-J were tested for cocarcinogenicity on the skin of noninbred Ha:ICR Swiss albino mice by application with 0.003% benzo[a]pyrene. Subfractions A-C and F-J showed significant cocarcinogenic activity; subfractions A, F, and H were the most active. Catechol was a major component of subfraction A and was also detected in subfractions B-D and F. Major components of the other subfractions included hydroquinone (B), coniferyl alcohol (C and H), hydroxyphenyl alcohols (D), alkyl-2-hydroxy-2-cyclopenten-1-ones (C, D, and F), hydroxyacetophenones (F), phenolic cyano compounds (F), and fatty acids (F). The results demonstrate the importance of catechol as a cocarcinogen in the weakly acidic fraction of cigarette smoke condensate and indicate the presence of other cocarcinogens.

Animals↗
PubMed1981

Comparative carcinogenicity and metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine in Syrian golden hamsters.

The tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) were tested for carcinogenic activity in Syrian golden hamsters. In Assay A, 30 hamsters were each given 19 s.c. injections of 0.048 mmol of NNK or NNN. In Assay B, 20 hamsters each received 75 s.c. injections of 0.012 mmol of NNK or NNN. Among the NNK-treated hamsters in Assay A, three developed carcinomas of the nasal cavity, and 19 had adenomas and/or adenocarcinomas of the lung. In the NNN group, one hamster developed a lung adenoma, and five had tracheal papillomas. In Assay B, 11 of the NNK-treated hamsters developed carcinomas of the nasal cavity, 16 had lung adenomas and/or adenocarcinomas, and seven had tracheal papillomas; in the NNN group, we recorded only one hamster with a lung adenoma and one with a tracheal papilloma. These findings in the Syrian golden hamster confirm that NNK is a more powerful carcinogen than NNN, as was shown previously in assays with rats and mice. In metabolism studies, 96 to 98% of the radioactivity of the injected [1-14C]NNK was recovered in the urine, 4% was recovered in the feces, and less than 0.5% was recovered as exhaled 14CO2. The corresponding distribution for [2'-14C]NNN was 62 to 78% in urine, 10% in feces, and less than 0.5% in respiratory 14CO2. The levels of binding of [1-14C]NNK and [2'-14C]NNN to the trichloroacetic acid-insoluble fractions were highest in liver, lung, kidney, and adrenals. The urinary metabolites of NNK and NNN resulted from alpha-hydroxylation, from N-oxidation of NNN to N'-nitrosonornicotine-1-N-oxide, and from reduction of NNK to 4-(methylnitrosamino)-1-(3-pyridyl)butan-1-ol.

Animals↗
PubMed1981

Differential effect of chronic ethanol consumption on the carcinogenicity of N-nitrosopyrrolidine and N'-nitrosonornicotine in male Syrian golden hamsters.

The effect of chronic ethanol consumption on the carcinogenicity of N'-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN) in male Syrian golden hamsters has been investigated. Groups of hamsters were maintained on either ethanol-containing or control liquid diets for 4 weeks prior to and during carcinogen treatment. NPYR or NNN was administered to ethanol-consuming or control hamsters by i.p. injection over a 25-week period in total doses of either 1 or 2 mmol. In the group treated with 1 mmol of NPYR and maintained on a control diet, we observed 1 of 20 hamsters with a nasal cavity tumor and 4 of 20 hamsters with tracheal tumors. In the group treated with 1 mmol of NPYR and maintained on the ethanol-containing diet, we observed 8 of 18 hamsters with nasal cavity tumors and 9 of 18 hamsters with tracheal tumors. The corresponding results in hamsters given 2 mmol of NPYR were: nasal cavity tumors, 14 of 21 (control) and 16 of 17 (ethanol); tracheal tumors, 8 of 21 (control) and 11 of 17 (ethanol). These results demonstrate that the carcinogenicity of NPYR is enhanced in ethanol-treated Syrian golden hamsters, particularly at the lower dose. In the groups treated with 1 mmol of NN and a control diet, we observed 1 of 21 hamsters with a nasal cavity tumor and 4 of 21 with tracheal tumors. In the corresponding ethanol-treated groups, we observed 1 of 17 hamsters with a nasal tumor and 5 of 17 with tracheal tumors. In the hamsters given 2 mmol of NNN, the results were: nasal cavity tumors, 5 of 21 (control) and 4 of 21 (ethanol); tracheal tumors, 9 of 21 (control) and 7 of 21 (ethanol). Thus, the carcinogenicity of NNN in the Syrian golden hamster was not affected by ethanol treatment. These results suggest that the metabolic activation of NPYR, but not that of NNN, may be enhanced by chronic ethanol consumption in the Syrian golden hamster.

Alcohol Drinking↗
PubMed1981

Reduction of tumorigenicity and of dihydrodiol formation by fluorine substitution in the angular rings of dibenzo(a,i)pyrene.

The tumor-initiating activities on mouse skin and in vitro metabolism of dibenzo(a,i)pyrene, 2-fluorodibenzo(a,i)pyrene, 3-fluorodibenzo(a,i)pyrene, and 2, 10-difluorodibenzo(a,i)pyrene were compared. After an initiating dose of 500 micrograms, followed by promotion with tetradecanoylphorbol acetate, dibenzo(a,i)pyrene induced skin tumors in 85% of the mice and caused 5.8 skin tumors/mouse. The corresponding tumorigenic activities for the fluorinated compounds were: 2-fluorodibenzo(a,i)pyrene (85%; 1.7 tumors/mouse); 3-fluorodibenzo(a,i)pyrene (80%; 3.1 tumors/mouse); and 2,10-difluorodibenzo(a,i)pyrene (10%; 0.1 tumors/mouse). After an initiating dose of 100 micrograms, only dibenzo(a,i)pyrene showed significant tumor-initiating activity. 3,4-Dihydro-3,4-dihydroxydibenzo(a,i)pyrene was identified as a metabolite of dibenzo(a,i)pyrene formed by the 9000 X g supernatant from the livers of Aroclor 1254-pretreated rats. Another dihydrodiol was tentatively identified as 1,2-dihydro-1,2-dihydroxydibenzo(a,i)pyrene. The formation of these angular ring dihdrodiols was inhibited in the metabolism of 2-fluorodibenzo(a,i)pyrene and 3-fluorodibenzo(a,i)pyrene. Angular ring dihydrodiols were not detected in the metabolism of 2,10-difluorodibenzo(a,i)pyrene. These results suggest that an angular ring dihydrodiol, 3,4-dihydro-3,4-dihydroxydibenzo(a,i)pyrene, which can form a bay-region dihydrodiol epoxide, may be a proximate carcinogen of dibenzo(a,i)pyrene.

Animals↗
PubMed1981

Metabolic alpha-hydroxylation of N-nitrosomorpholine and 3,3,5,5-tetradeutero-N-nitrosomorpholine in the F344 rat.

We studied the metabolism in the male F344 rats of N-nitrosomorpholine and of 3,3,5,5-tetradeutero-N-nitrosomorpholine ; the latter is less carcinogenic and less mutagenic than is N-nitrosomorpholine. alpha-Hydroxylation (3- or 5-hydroxylation) of N-nitrosomorpholine by liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system produced (2-hydroxyethoxy)acetaldehyde, which was identified as its 2,4-dinitrophenylhydrazone derivative. When we administered N-nitrosomorpholine to rats i.p., we did not detect (2-hydroxyethoxy)acetaldehyde in the urine, but we did identify (2-hydroxyethoxy)acetic acid (16% of the dose). We also identified N-nitroso(2-hydroxyethyl)glycine (33% of the dose) from beta-hydroxylation (2- or 6-hydroxylation), N-nitrosodiethanolamine (12%), and unchanged N-nitrosomorpholine (1.5%) in the urine. The deuterated analogs of the above metabolites were isolated from the urine of rats treated with 3,3,5,5-tetradeutero-N-nitrosomorpholine in yields as follows: (2-hydroxyethoxy)acetic acid (3.4%); N-nitroso(2-hydroxyethyl)glycine (37%); N-nitrosodiethanolamine (12%); N-nitrosomorpholine (0.4%). These data demonstrates that deuterium substitution in the alpha-positions of N-nitrosomorpholine caused a decrease in the extent of alpha-hydroxylation and indicate that alpha-hydroxylation is the mechanism of activation of N-nitrosomorpholine.

Animals↗
PubMed1980

Metabolic beta-hydroxylation and N-oxidation of N'-nitrosonornicotine.

3'-Hydroxy-N'-nitrosonornicotine (2), 4'-hydroxy-N'-nitrosonornicotine (3), N'-nitrosonornicotine 1-N-oxide (4) were synthesized and identified as metabolites in the F-344 rat of the tobacco-specific carcinogen N'-nitrosonornicotine (1). For the synthesis of 2, myosmine (5) was converted to 3'-bromomyosmine (6). Displacement by acetate and hydrolysis gave 3'-hydroxymyosmine (7), which was reduced and nitrosated to give 2. 4'-Hydroxymyosmine (13), the precursor to 3, was prepared by ammonolysis of 1,2-epoxy-4-(N-morpholino)-4-(3-pyridyl)-4-cyanobutane (10). N'-Nitrosonornicotine 1-N-oxide (4) was prepared by m-chloroperbenzoic acid oxidation of 1. When 1 was incubated with liver microsomes from Aroclor-pretreated F-344 rats, trace amounts of 2 and 3 were produced and 4 was a major metabolite. The urine from rats treated with N'-nitrosonornicotine-2'-14C contained only trace amounts of 2 and 3, whereas 4 accounted for 6.7-9.4% of the dose.

Animals↗
PubMed1980

Identification of mutagenic dihydrodiols as metabolites of benzo(j)fluoranthene and benzo(k)fluoranthene.

The metabolism of the environmental agents benzo(j)-fluoranthene and benzo(k)fluoranthene was investigated using supernatants from the livers of Aroclor 1254-pretreated rats, which are effective in activating benzo(j)fluoranthene and benzo(k)fluoranthene to metabolites mutagenic toward Salmonella typhimurium TA 100. Six bands of metabolites of benzo(j)fluoranthene were separated by high-pressure liquid chromatography, and each band was tested for mutagenicity toward S. typhimurium TA 100 with activation. The major mutagenic band contained two dihydrodiols, one of which was identified as 9,10-dihydro-9, 10-dihydroxybenzo(j)fluoranthene by comparison to a synthetic reference standard. 9,10-Dihydro-9,10-dihydroxybenzo(j)fluoranthene was mutagenic toward S. typhimurium TA 100 with activation, presumably as a result of conversion to the corresponding dihydrodiol-epoxide. The major dihydrodiol metabolite of benzo(k)fluoranthene was identified, by comparison to a synthetic standard, as 8,9-dihydro-8,9-dihydroxybenzo(k)fluoranthene. This dihydrodiol, which could also be converted to a dihydrodiol-epoxide, was mutagenic toward S. typhimurium TA 100 with activation. The results of this study indicate that metabolism to dihydrodiols is one pathway in the activation of benzo(j)fluoranthene and benzo(k)fluoranthene to ultimate mutagens for S. typhimurium TA 100.

Animals↗
PubMed1980

Assays for metabolic alpha-hydroxylation of N'-nitrosonornicotine and N-nitrosopyrrolidine and the influence of modifying factors.

High-pressure liquid chromatographic methods were developed to study microsomal alpha-hydroxylation, which is likely to be an activation mechanism for N-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN). The effects of ethanol, phenobarbital and 3-methylcholanthrene pretreatment on the alpha-hydroxylation of NPYR and NNN were determined using F-344 rats and Syrian golden hamsters. In the rat, 3-methylcholanthrene pretreatment decreased the rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN, but increased the rate of 2'-hydroxylation of NNN. Phenobarbital pretreatment of rats did not markedly affect rates of alpha-hydroxylation of NPYR or NNN. In the hamster, 3-methylcholanthrene pretreatment increased the rate of alpha-hydroxylation of NPYR, but did not affect the rates of alpha-hydroxylation of NNN. Phenobarbital or ethanol pretreatment of hamsters resulted in increased rates of alpha-hydroxylation of NPYR and 5'-hydroxylation of NNN. The induction of alpha-hydroxylation of NNN and NPYR by ethanol suggests that these nitrosamines may be more carcinogenic in alcohol-treated animals.

Animals↗
PubMed1980

Chemical studies on tobacco smoke LXVIII. Analysis of volatile and tobacco-specific nitrosamines in tobacco products.

The yields of volatile N-nitrosamines in cigarette smoke are primarily dependent upon the nitrate content of the tobacco and, to some extent, on the protein content. Cellulose acetate tips, such as those found on most commercial filter cigarettes, selectively remove at least 70% of the volatile N-nitrosamines, independently of the pH of the weakly acidic or weakly alkaline smoke. So far, three tobacco-specific N-nitrosamines have been detected in tobacco and tobacco smoke. During tobacco processing and smoking, N'-nitrosonornicotine is formed by nitrosation of nicotine and, to a minor degree, by nitrosation of nornicotine, whereas 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone originates from oxidative nitrosation of nicotine. N'-Nitrosoanatabine is formed by nitrosation of the second most abundant tobacco alkaloid, anatabine. The tobacco-specific N-nitrosamines in the smoke arise partly from the tobacco by transfer and partly by nitrosation of the alkaloids during smoking (pyrosynthesis). Preliminary results indicate that cellulose acetate filter tips may selectively remove considerable amounts of the nonvolatile nitrosamines from the smoke.

Chromatography, High Pressure Liquid↗
PubMed1980

Metabolism of the tobacco specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.

The metabolism, in the F-344 rat, of the tobacco-specific carcinogens, N'-nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was studied. NNN was hydroxylated at each position of the pyrrolidine ring; 2'-hydroxylation gave 4-hydroxy-1-(3-pyridyl)-1-butanone in vitro and the corresponding acid in vivo, 3'-hydroxylation gave 3'-hydroxyNNN, 4'-hydroxylation gave 4'-hydroxy-NNN and 5'-hydroxylation gave 4-hydroxy-4-(3-pyridyl)butanal (in vitro) and 4-hydroxy-4-(3-pyridyl) butanoic acid (in vivo). The principle ring hydroxylation in the untreated F-344 rat was 5'-hydroxylation. Pyridine N-oxidation was also observed, giving NNN-1-N-oxide as a major metabolite. The principle urinary metabolites of NNN were formed by 5'-hydroxylation and pyridine-N-oxidation. For NNK, a major process was reduction of the carbonyl to give 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanol. alpha-Hydroxylation of both the N-methyl and N-methylene groups was also observed, as was formation of NNK-N-oxide in vitro and in vivo.

Animals↗
PubMed1980

Comparative carcinogenicity in F344 rats of the tobacco-specific nitrosamines, N'-nitrosonornicotine and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone.

The tobacco-specific carcinogens, N'-nitrosonornicotine (NNN) and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were tested for carcinogenicity in F344 rats. Each nitrosamine in trioctanoin was administered by s.c. injection to 12 male and 12 female rats over a period of 20 weeks. The total dose of each nitrosamine was 3.4 mmol. The experiment was terminated after 12 months. NNK induced nasal cavity tumors in 83% of the males and in 83% of the females, liver tumors in 83% of the males and in 100% of the females, and lung tumors in 67% of the males and in 67% of the females. NNN induced nasal cavity tumors in 92% of the males and in 75% of the females. Only one liver tumor and no lung tumors were observed in the NNN-treated rats. These results indicate that, in the F344 rat, NNK is a more powerful carcinogen than is NNN.

Animals↗
PubMed1980

Tumor-initiating activity of dihydrodiols formed metabolically from 5-methylchrysene.

The major dihydrodiols formed from 5-methylchrysene by rat liver 9000 X g supernatant were tested for tumor-initiating activity on mouse skin. The compounds tested were 1,2-dihydro-1,2-dihydroxy-5-methylchrysene, 7,8-dihydro-7,8-dihydroxy-5-methylchrysene, 9,10-dihydro-9,10-dihydroxy-5-methylchrysene, and 5-methylchrysene. Each compound was applied in a total initiating dose of 30 microgram and was followed by promotion with tetradecanoylphorbol acetate. 1,2-Dihydro-1,2-dihydroxy-5-methylchrysene was the most powerful tumor initiator, inducing tumors in 95% of the animals and 7.3 tumors per animal. 5-Methylchrysene and 7,8-dihydro-7,8-dihydroxy-5-methylchrysene induced tumors in 75 and 50% of the animals and gave 3.0 and 1.1 tumors per animal, respectively. 9,10-Dihydro-9,10-dihydroxy-5-methylchrysene was not tumorigenic. The results indicate that 1,2-dihydro-1,2-dihydroxy-5-methylchrysene is a major proximate carcinogen of 5-methylchrysene. Both 1,2-dihydro-1,2-dihydroxy-5-methylchrysene and 7,8-dihydro-7,8-dihydroxy-5-methylchrysene can theoretically form bay-region dihydrodiol epoxides, but the former was more tumorigenic than the latter. The high activity of 1,2-dihydro-1,2-dihydroxy-5-methylchrysene is typical of hydrocarbon derivatives with a methyl group in the bay region adjacent to an unsubstituted angular ring.

Animals↗
PubMed1980

Metabolism in the F344 rat of 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, a tobacco-specific carcinogen.

The metabolism of the tobacco-specific carcinogen, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was studied in the F344 rat, in which it induces tumors of the nasal cavity, liver, and lung. When NNK was incubated with rat liver microsomes and a reduced nicotinamide adenine dinucleotide phosphate-generating system, metabolites resulting from alpha-hydroxylation, carbonyl reduction, and N-oxidation were isolated. alpha-Hydroxylation at the methylene carbon gave 4-oxo-4-(3-pyridyl)butanal, whereas alpha-hydroxylation at the methyl carbon gave myosmine and 4-hydroxyl-1-(3-pyridyl)butan-1-one. The formation of these products involved the intermediacy of electrophilic diazohydroxides or carbonium ions which may be proximate or ultimate carcinogens of NNK. Carbonyl reduction gave 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and N-oxidation yielded 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1-butanone. When rats were gavaged with NNK, the microsomal products of alpha-hydroxylation were not detected in the 48-hr urine. Compounds which presumably resulted from further oxidation or reduction of these products, 4-oxo-4-(3-pyridyl)butyric acid, 4-hydroxy-4-(3-pyridyl)butyric acid, and 4-hydroxy-1-(3-pyridyl)butan-1-ol, were isolated. 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)butan-1-ol and 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl-N-oxide)-1 butanone were also urinary metabolites.

Animals↗
PubMed1979

Alpha-hydroxylation of N-nitrosopyrrolidine and N'-nitrosonornicotine by human liver microsomes.

The environmental carcinogens N-nitrosopyrrolidine (NPYR) and N'-nitrosonornicotine (NNN) were incubated with human liver microsomes to test for the presence of enzymes catalyzing alpha-hydroxylation, which is likely to be an activation mechanism for these compounds. Both nitrosamines underwent alpha-hydroxylation; rates were higher for NPYR than for NNN, as observed in rats. The results indicate that both NPYR and NNN can be metabolically activated by human liver microsomes.

Humans↗
PubMed1979

Tumor initiating activity of 5,11-dimethylchrysene and the structural requirements favoring carcinogenicity of methylated polynuclear aromatic hydrocarbons.

The tumor initiating activities of 5,11-dimethylchrysene and 5-methylchrysene on mouse skin were compared. After initiating doses of 30 microgram or 10 microgram, with promotion by 3 times weekly applications of tetradecanoylphorbol acetate, both compounds were highly tumorigenic, inducing tumors in 70--85% of the treated animals. Since 5,12-dimethylchrysene had previously been shown to be only a weak tumor initiator, these results support the generalization that the structural requirements favoring carcinogenicity among the methylated chrysenes and other polynuclear aromatic hydrocarbons (PAH) are a bay region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.

Animals↗