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S S Hecht

Publications and source records attributed to S S Hecht.

At least 343 records · Page 19Linked to original sources
PubMed1977

Kinetics of nornicotine and anabasine nitrosation in relation to N'-nitrosonornicotine occurrence in tobacco and to tobacco-induced cancer.

The kinetics of nornicotine and anabasine nitrosation, studied in aqueous solution, obeyed equations typical for the nitrosation of aliphatic secondary amines, with third-order stoichiometric rate constants of 1.15 (nornicotine) and 0.86 (anabasine) M-2 sec-1. The similarity of the two rate constants suggested that the nitrosonornicotine occurring in tobacco arises from nicotine rather than nornicotine, because tobacco contains anabasine but apparently does not contain nitrosoanabasine. The high rate constants suggested that in vivo nitrosation of these secondary amines may constitute a hazard to tobacco smokers and chewers, in addition to that presented by preformed nitrosonornicotine.

Anabasine↗
PubMed1976

Chemical studies on tobacco smoke. XLII. Nitrosonornicotine: presence in tobacco, formation and carcinogenicity.

NNN is the first organic carcinogen isolated from unburned tobacco. It has been found in smoking tobaccos, chewing tobaccos and in snuff in concentrations between 0.3 and 90.0 mug. This appears to be an unusually high concentration for a nitrosamine in an environmental agent. We have presented data which suggest that NNN, and possibly other unknown nitrosamines, are formed during the curing of tobacco and that the nitrate content of tobacco is an important factor in nitrosamine formation. Studies with N'-methylanabasine applied to tobacco plants are currently under way to test the idea that nicotine rather than nornicotine is the major precursor of NNN in processed tobacco. In mice, NNN induces adenomas of the lung. Bioassays with rats have shown that NNN is carcinogenic to the oesophagus and the nasal cavity. These chemical and biological data are consistent with the observation that tobacco chewers face an increased risk of cancer of the oesophagus. This observation does not, of course, rule out the possibility that other tobacco carcinogens are responsible for the increased cancer risk of tobacco chewers.

Animals↗
PubMed1975

Chemical studies on tobacco smoke. XXXIII. N' -nitrosonornicotine in tobacco: analysis of possible contributing factors and biologic implications.

A chemical analytic method to determine N'-nitrosonornicotine (NNN) and N' -nitrosoanabasine (NAB) in tobacco was developed. NNN was found in the unburned tobacco of commercial products at concentrations betweeen 0.3 and 88.6 mug/g. The highest levels were observed in highly fermented snuff (29.1 mug/g) and fine-cut chewing tobacco (88.6 mug/g). NAB was not detected (smaller than 0.5 ng/g) in any tobacco examined. Two new tobacco components, N' -carbomethoxynornicotine and N' -carbomethoxyanabasine,were found. Possible origins of NNN in tobacco were discussed, especially in relation to concentrations of nitrite, nitate, and alkaloids, and in relation to pH and curing. Biologic implications, including the possible function of NNN (the first organic carcinogen isolated from unburned tobacco) as a causative factor in cancer of the oral cavity in tobacco chewers and betel quid chewers, were also discussed.

Alkaloids↗
PubMed1975

A study of tobacco carcinogenesis. XIV. Effects of N'-nitrosonornicotine and N'-nitrosonanabasine in rats.

N'-Nitrosonornicotine (NNN) and N'-nitrosoanabasine (NAB) were synthesized and administered in drinking water to male Fischer rats for 30 weeks (total dose, 630 mg). 1,4-Dinitrosopiperazine (DNPI) served as the positive control. By 11 months, all surviving rats given NNN developed esophageal tumors (12/20); 1 had a pharyngeal tumor and 3 had invasive carcinomas originating in the nasal cavity. During the same time, only 1 of 20 rats given NAB developed esophageal tumors. Compared to the strong esophageal carcinogen DNPI, NNN was a moderately active and NAB a weak carcinogen. NNN (0.3-90 parts per million) in chewing tobacco was related to the observation that cancer of the oral cavity and esophagus in man was correlated with the chewing of tobacco.

Anabasine↗
PubMed1975

A study of tobacco carcinogenesis. XIII. Tumor-promoting subfractions of the weakly acidic fraction.

The weakly acidic fraction (WAF) of cigarette smoke particulate matter was fractioned by silica get chromatography. We assayed the various primary subfractions for potential tumor-promoting activity by measuring the incorporation of tritiated thymidine into mouse epidermal DNA as induced by these subfractions. Based on these results and on chemical composition, the primary subfractions, were then combined into four major subfractions and tested on initiated mouse skin for tumor-promoting activity by long-term application. Two of these subfractions (40% of WAF) were inactive, whereas the other two (18 and 35% of WAF) showed tumor-promoting activity. The two active portions were then further chromatographed and tested by the short-term bioassay. Some major components of the resulting active fractions included alkyl-2-cyclopenten-2-ol-1-ones, catechols, hydroquinone, fatty acids, and 3-hydroxypyridines. Among these components, catechol, hydroquinone, 3-hydroxypyridine, 6-methyl-3-hydroxypyridine, linolenic acid, and linoleic acid were inactive as tumor promoters in the experimental animal. The activity of the alkyl-2-cyclopenten-2-ol-1-ones is unknown. Other components remain to be identified.

Animals↗
PubMed1974

N'-nitrosonornicotine in tobacco.

N'-Nitrosonornicotine, a potential carcinogen, has been positively identified in unburned tobacco. The amount in commercial U.S. tobacco products is between 1.9 to 88.6 parts per million, one of the highest values of an environmental nitrosamine yet reported. The amount in food and drink rarely exceeds 0.1 part per million. This compound is the first example of a potential organic carcinogen isolated from tobacco.

Carcinogens↗
PubMedDate not supplied

Carcinogen-derived biomarkers and lung cancer.

Carcinogen-derived biomarkers are substances such as metabolites or macromolecular adducts that are derived from specific identifiable carcinogens and can be quantified in human tissues or body fluids. With respect to lung cancer, the most important carcinogen-derived biomarkers presently being studied are those derived from the lung carcinogens in tobacco smoke-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and polynuclear aromatic hydrocarbons. Some examples of these biomarkers and their application are discussed.

Biomarkers, Tumor↗
PubMedDate not supplied

Mutagenicity of K-region derivatives of 1-nitropyrene; remarkable activity of 1- and 3-nitro-5H-phenanthro[4,5-bcd]pyran-5-one.

The mutagenic activities toward S. typhimurium strains TA98 and TA100 of K-region derivatives of 1-nitropyrene and pyrene were determined. The compounds tested were trans-4,5-dihydro-4,5-dihydroxy-1-nitropyrene (Compound 3), trans-4,5-dihydro-4,5-dihydroxypyrene (Compound 4), 1-nitropyrene-4,5-quinone (Compound 5), 1-nitropyrene-9,10-quinone (Compound 6), pyrene-4,5-quinone (Compound 7), and the lactones, 1-nitro-5H-phenanthro[4,5-bcd]pyran-5-one (Compound 8), 3-nitro-5H-phenanthro[4,5-bcd]pyran-5-one (Compound 9), and 5H-phenanthro[4,5-bcd]pyran-5-one (Compound 10). Neither pyrene nor any of its K-region derivatives was mutagenic, either in the absence or presence of S9 mix at the doses tested. Of the K-region derivatives of 1-nitropyrene, the lactones (Compounds 8 and 9) were generally the most active; 0.25 microgram/plate induced 900-2200 revertants in TA98 or TA100 without activation. The 4,5-dihydrodiol (Compound 3), an established mammalian metabolite of 1-nitropyrene, was less mutagenic than was 1-nitropyrene in TA98, but was more mutagenic than was 1-nitropyrene in TA100, regardless of the presence of S9 mix. The quinones (Compounds 5 and 6) were less mutagenic than was 1-nitropyrene in the absence of S9 mix in both strains, but their activities were increased in the presence of S9 mix. The mutagenic activities of the lactones (Compounds 8 and 9) were lower in strains TA98NR and TA98/1,8-DNP6 than in TA98, indicating that nitro-reduction and esterification are involved in their activation. The results of this study indicate that K-region derivatives of 1-nitropyrene may be important in its metabolic activation.

Animals↗
PubMedDate not supplied

Comparative carcinogenicity of o-toluidine hydrochloride and o-nitrosotoluene in F-344 rats.

o-Toluidine hydrochloride and one of its metabolites, o-nitrosotoluene, were administered in the diet (0.028 mol/kg diet) to 2 groups of 30 male F-344 rats for 72 weeks. o-Nitrosotoluene induced significantly more tumors of the bladder (16/30 rats) and liver (20/30) than did o-toluidine hydrochloride (bladder, 4/30; liver, 3/30. Both compounds induced comparable numbers of peritoneal tumors and fibroma of the skin and spleen. o-Toluidine hydrochloride induced more mammary tumors (13/30) than did o-nitrosotoluene (3/30). The results indicate tha N-oxidation is important in the induction of bladder and liver tumors by these single ring compounds but that other mechanisms could be involved in the induction of peritoneal, skin, spleen and mammary tumors.

Animals↗
PubMedDate not supplied

A study of tobacco carcinogenesis. XLII. Bioassay in A/J mice of some structural analogues of tobacco-specific nitrosamines.

The tumorigenic activities in A/J mouse lung of the tobacco-specific nitrosamines, N'-nitrosonornicotine (NNN), 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and several structural analogues were evaluated. The analogues were N-nitrosopyrrolidine (NPYR), 5'-carboxy-N'-nitrosonornicotine (CNNN), N-nitrosoproline (NPRO) and 1-(3-pyridyl)-2-buten-1-one (PBO). The results were as follows (dose in mumol per mouse/lung tumors per mouse): NNN (100/1.8 +/- 1.4); NPYR (100/3.9 +/- 1.5); CNNN (200/0.3 +/- 0.5); CNNN (100/0.5 +/- 0.6); NPRO (100/0.6 +/- 0.7); NNK (20/7.2 +/- 3.4); PBO (20/0.7 +/- 1.0); saline control (0.0.5 +/- 0.7). Several conclusions were drawn from this assay. NNK and NPYR were more tumorigenic than NNN. CNNN was non-tumorigenic and thus appears to have potential as a monitor for endogenous formation of tobacco-specific nitrosamines. The alpha,beta-unsaturated ketone PBO does not appear to be an ultimate tumorigen of NNK or NNN.

Adenoma↗
PubMedDate not supplied

Identification of crotonaldehyde as a hepatic microsomal metabolite formed by alpha-hydroxylation of the carcinogen N-nitrosopyrrolidine.

Crotonaldehyde (2-butenal), which reacts with DNA and is mutagenic and carcinogenic, was identified as a hepatic microsomal metabolite of the hepatocarcinogen N-nitrosopyrrolidine. Incubation mixtures of N-nitrosopyrrolidine, cofactors, and hepatic microsomes from Aroclor pretreated or control F344 rats were derivatized with (2,4-dinitrophenyl)hydrazine reagent and the resulting mixtures analyzed by high-performance liquid chromatography. Crotonaldehyde (2,4-dinitrophenyl)hydrazone was identified by its retention time in two different systems and by its ultraviolet and mass spectrum. The ratio of 4-hydroxybutyraldehyde, which has previously been identified as a metabolite of NPYR, to crotonaldehyde was 1.5-2 over a range of substrate concentrations. The approximate values of Km and nu max for crotonaldehyde were 5.8 mM and 0.6 nmol/min/mg of protein and for 4-hydroxybutyraldehyde 14.1 mM and 1.7 nmol/min/mg of protein, for substrate concentrations between 1 and 8 mM, with microsomes from Aroclor pretreated rats. The ratio of 4-hydroxybutyraldehyde to crotonaldehyde was 1.9 upon esterase-catalyzed solvolysis of alpha-acetoxy-N-nitrosopyrrolidine, a stable precursor to the initial product of N-nitrosopyrrolidine alpha-hydroxylation. These results demonstrate that crotonaldehyde is formed upon metabolic alpha-hydroxylation of N-nitrosopyrrolidine and suggest that it may be involved in N-nitrosopyrrolidine-macromolecule interactions.

Aldehydes↗
PubMedDate not supplied

Metabolism and DNA binding of 1-nitropyrene and 1-nitrosopyrene in newborn mice.

This study was carried out in order to evaluate possible mechanisms responsible for tumor induction by 1-nitropyrene and to provide insights on the higher tumorigenicity of 1-nitrosopyrene than 1-nitropyrene in newborn mouse liver. The "ground mouse" technique was used to follow the development of the metabolism of 1-nitropyrene and 1-nitrosopyrene in newborn and infant mice in vivo. Equimolar doses of 1-nitropyrene and 1-nitrosopyrene were used as in the bioassay reported previously. The compounds were administered by ip injection (100 nmol, day 1; 200 nmol, day 8; 400 nmol, day 15). The ethyl acetate soluble metabolites of 1-nitropyrene were identified as 1-aminopyrene, trans-4,5-dihydro-4,5-dihydroxy-1-nitropyrene, 1-nitropyren-3-ol, 1-nitropyren-6-ol, and 1-nitropyren-8-ol on the basis of cochromatography with synthetic standards in two different HPLC systems. Nitroreduction of 1-nitropyrene to 1-aminopyrene was observed only in 1 day old mice. Ethyl acetate soluble metabolites of 1-nitrosopyrene were identified as 1-aminopyrene and 1-nitropyrene. The capacity of 1 day old mice to metabolize 1-nitropyrene and 1-nitrosopyrene exceeded those of 8 and 15 day old mice. The extent of nitroreduction of 1-nitrosopyrene exceeded that of 1-nitropyrene. A major DNA adduct, N-(deoxyguanosin-8-yl)-1-aminopyrene, was identified and quantified in liver and in lung, 24 h after carcinogen treatment. The extents of formation of this adduct (pmol/mg of DNA, mean of two experiments) were as follows: 1-nitropyrene (liver, 4.1; lung, 1.2); 1-nitrosopyrene (liver, 30.4; lung, 6.3).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Synthesis and tumor-initiating activities of dimethylchrysenes.

Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5,7-dimethylchrysene+ ++ (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.

Animals↗
PubMedDate not supplied

Analysis for N2-(pyridyloxobutyl)deoxyguanosine adducts in DNA of tissues exposed to tritium-labeled 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine.

The tobacco-specific carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are metabolically activated to DNA binding intermediates, partially via 4-(3-pyridyl)-4-oxobutanediazohydroxide (7) or related carbonium ions. Previous studies have shown that generation of 7 from 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone (11) in the presence of deoxyguanosine yields a major adduct identified as 2'-deoxy-N-[1-methyl-3-oxo-3-(3-pyridyl)propyl]guanosine (adduct 1). These results suggested that adduct 1 should be present in DNA of tissues that can metabolically activate NNK and NNN. In the present study, we evaluate the formation of adduct 1 and its structurally related straight-chain analogue 2'-deoxy-N-[4-oxo-4-(3-pyridyl)butyl]guanosine (adduct 2) in DNA of tissues of rats treated with [5-3H]NNK or [5-3H]NNN, and in DNA of nasal mucosa that had been cultured in medium containing [5-3H]NNK or [5-3H]NNN. Hepatic DNA from rats treated with [5-3H]NNK was enzymatically hydrolyzed to deoxyribonucleosides and analyzed by HPLC. One of the radioactive peaks, peak E, coeluted with adduct 1. However, treatment of peak E with NaBH4 resulted in the formation of products different from those produced by NaBH4 treatment of adduct 1, demonstrating that adduct 1 could not be detected under these conditions. Hydrolysis of peak E with acid produced 4-hydroxy-1-(3-pyridyl)-1-butanone (9), suggesting that peak E might be adduct 2. Therefore, adduct 2 was synthesized by reaction of deoxyguanosine with 1-(3-pyridyl)butane-1,4-dione (5) in the presence of NaCNBH3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗