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Biomedical subjects

S S Hecht

Publications and source records attributed to S S Hecht.

At least 235 records · Page 13Linked to original sources
PubMed1985

On the analysis of 1-nitronaphthalene, 1-nitropyrene and 6-nitrochrysene in cigarette smoke.

A method was developed for the analysis of 1-nitronaphthalene, 1-nitropyrene, and 6-nitrochrysene in mainstream cigarette smoke, using [14C]1-nitronaphthalene, [14C]1-nitropyrene, and [14C]6-nitrochrysene as tracers and internal standards. Cigarette smoke condensate was collected and the appropriate fractions containing the labelled standards were obtained by a series of solvent partitions and column chromatography. Recovery of internal standards ranged from 60 to 70%. The fractions were analyzed by capillary gas chromatography with electron capture detection and by combined capillary gas chromatography-mass spectrometry. 1-Nitronaphthalene (less than 10 ng/cigarette), 1-nitropyrene (less than 10 ng/cigarette), and 6-nitrochrysene (less than 1 ng/cigarette) were not detected in the mainstream smoke of the University of Kentucky 1R1 cigarette, a US commercial 85 mm non-filter cigarette, or a French commercial 70 mm non-filter cigarette.

Chromatography, Gas↗
PubMed1985

Effects of dietary indoles and isothiocyanates on N-nitrosodimethylamine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone alpha-hydroxylation and DNA methylation in rat liver.

Dietary-related indoles, isothiocyanates, and the allyl isothiocyanate glucosinolate, sinigrin, were administered to F344 rats in the diet for 2 weeks (chronic protocol) or by gavage 2 h before sacrifice (acute protocol) and the effects of these pretreatments on the alpha-hydroxylation of two carcinogenic nitrosamines, N-nitrosodimethylamine (NDMA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), were evaluated. alpha-Hydroxylation was measured in vitro by quantitation of formaldehyde formation upon incubation of the nitrosamines with liver microsomes, and in vivo by quantitation of levels of 7-methylguanine and O6-methylguanine in hepatic DNA, 4 h after nitrosamine treatment. Compounds shown to be inhibitory in the in vitro assay were selected to be further evaluated using the in vivo assay. The results of the in vitro assays showed that indoles were inducers of the demethylation of both nitrosamines. Indole, L-tryptophan and indole-3-carbinol were strong inducers of NDMA and NNK demethylation, respectively. In contrast, isothiocyanates such as phenethyl isothiocyanate and phenyl isothiocyanate demonstrated a wide range of inhibitory activities toward demethylation of these nitrosamines in both the acute and chronic studies. Chronic, but not acute, pretreatment with sinigrin also caused a significant decrease in the demethylation of NDMA and NNK. In view of their promising inhibitory activities, the effects of phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin on the in vivo methylation of DNA by NDMA and NNK were evaluated. The results were parallel to those obtained in the in vitro assays. Phenethyl isothiocyanate, phenyl isothiocyanate and sinigrin generally inhibited the formation of 7-methylguanine and O6-methylguanine in rat hepatic DNA. The results of this study suggest that these compounds could be anticarcinogenic to NDMA and NNK.

Animals↗
PubMed1985

Mutagenicity and tumor initiating activity of methylated benzo[b]fluoranthenes.

The mutagenicity toward S. typhimurium TA 100 and tumor initiating activity on mouse skin of benzo[b]fluoranthene (BbF), 1-methylbenzo[b]fluoranthene (1-MeBbF), 3-MeBbF, 7-MeBbF, 8-MeBbF, 9-MeBbF, 12-MeBbF, 5,6-dimethylbenzo[b]fluoranthene (5,6-diMeBbF) and 1,3-diMeBbF were assayed. Dose-dependent mutagenic activity was observed for BbF, 3-MeBbF, and 1,3-diMeBbF; the other compounds were inactive at the doses tested. 3-MeBbF and 1,3-diMeBbF were strong tumor initiators, with activity greater than that of BbF. All the other compounds were less tumorigenic than BbF. The results suggest that the structural features favoring tumorigenicity of methylated non-alternant polynuclear aromatic hydrocarbons such as BbF are different from those favoring tumorigenicity of methylated alternant polynuclear aromatic hydrocarbons such as benzo[a]pyrene, chrysene and benz[a]anthracene.

Animals↗
PubMed1985

Study of DNA methylation by tobacco-specific N-nitrosamines.

An enzyme-linked immunosorbent assay (BA-ELISA) involving use of biotin-labeled anti-rabbit IgG and avidin-labeled horseradish peroxidase was developed for the measurement of O6-methyl-2'-deoxyguanosine (O6-MedGuo). Up to 5 micrograms of methylated DNA was enzymatically hydrolyzed, and the extent of inhibition of binding of immobilized O6-MedGuo-bovine serum albumin to rabbit anti-O6-MedGuo was measured. Fifty percent inhibition of antigen-antibody binding was achieved with 2.5 pmole of of O6-MedGuo. Separation of O6-MedGuo from unmodified nucleosides by high-performance liquid chromatography (HPLC-BA-ELISA) allowed detection of 700 fmole O6-MedGuo in 1 mg of DNA. Among the tobacco-related carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent. In F344 rats it induces nasal cavity, lung and liver tumors. Four hours after a single IV injection of NNK to F344 rats (87 mg/kg body weight), O6-MedGuo was present in target organs (mumole O6-MedGuo/mole dGuo) (nasal mucosa, 219; lung, 13.2; and liver, 34.5) but was not detectable in nontarget organs. F344 rats receiving daily IP injections of NNK (40 mg/kg body weight) for 14 days were sacrificed 24 hr after the last injection. The levels of (O6-Medguo/dGuo) were 7.9 and 11.4 mumole/mole in the nasal mucosa and lung, respectively. In the liver no O6-MedGuo was detected, but 1050 mumole of 7-MeGua/mole Gua was measured by HPLC-fluorimetry. No DNA methylation was observed in the nasal mucosa or liver of F344 rats treated with the nicotine-derived carcinogen N'-nitrosonornicotine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Tumorigenicity of 5-methylchrysene dihydrodiols and dihydrodiol epoxides in newborn mice and on mouse skin.

5-Methylchrysene, (+/-)-trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene, (+/-)-trans-7,8-dihydro-7,8-dihydroxy-5-methylchrysene, (+/-)-trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-DE-I), (+/-)-trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (syn-DE-I), and (+/-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene (anti-DE-II) were tested for tumorigenicity in newborn mice and for tumor-initiating activity on mouse skin. In newborn mice, a total dose of 56 nmol of anti-DE-I induced 4.6 lung tumors/mouse and 1.2 liver tumors/mouse. These incidences were significantly higher than observed for any of the other metabolites, tested at equimolar doses. The results indicate that anti-DE-I, but not syn-DE-I or anti-DE-II, is a major ultimate carcinogen of 5-methylchrysene in the newborn mouse. Anti-DE-I was also more tumorigenic than anti-DE-II on mouse skin, inducing 4.4 tumors/mouse after an initiating dose of 100 nmol, compared to zero tumors per mouse induced by anti-DE-II. However, anti-DE-I was less tumorigenic on mouse skin than was its metabolic precursor, trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene or its parent hydrocarbon, 5-methylchrysene.

Animals↗
PubMed1985

Chemical carcinogenesis: an overview.

A brief review is presented of some types of chemical carcinogens and their metabolic activation to DNA-binding intermediates, and of the influence of modifiers of carcinogenesis on the probability of tumor development. The relationship between human exposure to one group of carcinogens--the tobacco specific nitrosamines--and the development of tobacco-related cancers is discussed.

Carcinogens, Environmental↗
PubMed1985

Rates of hydrolysis and extents of DNA binding of 5-methylchrysene dihydrodiol epoxides.

The rates of hydrolysis in the absence and presence of native and denatured DNA, and the extents of DNA binding of five dihydrodiol epoxides derived from 5-methylchrysene (5-MeC) and chrysene have been determined. The compounds studied were: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-Mec; trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC; trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC; and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene. In the absence of DNA, at pH 7 and 37 degrees C half-lives of trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC and trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC were similar, t 1/2 = 62 and 59 min, while trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC hydrolyzed faster than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC, t 1/2 = 5.4 versus 17.5 min; trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene had the slowest rate of hydrolysis, t 1/2 = 104 min. Studies of the effects of native and denatured DNA on the rates of hydrolysis of the dihydrodiol epoxides indicated that native DNA remarkably accelerated these rates for all dihydrodiol epoxides, but the degree of acceleration varied for the different dihydrodiol epoxides. The acceleration of hydrolytic rates by native DNA relative to that by denatured DNA was correlated with the covalent binding of these dihydrodiol epoxides with DNA in vitro. The catalytic effect of DNA in enhancing the rates of hydrolysis of dihydrodiol epoxides and the relative extents of covalent binding of the dihydrodiol epoxides to DNA were in the following order: trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC greater than trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene greater than trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-MeC greater than trans-7,8-dihydroxy-syn-9,10-epoxy-7,8,9,10-tetrahydro-5-MeC. The results of this study suggest that physical interactions with DNA are important in determining the relative extents of binding of these dihydrodiol epoxides to DNA in vitro.

Chromatography, High Pressure Liquid↗
PubMed1985

Comparative metabolic activation in mouse skin of the weak carcinogen 6-methylchrysene and the strong carcinogen 5-methylchrysene.

We compared the metabolic activation in mouse skin of the weak carcinogen 6-methylchrysene, which lacks a bay region methyl group, and the strong carcinogen 5-methylchrysene, which has a bay region methyl group. Metabolites of 6-methyl-chrysene were prepared using liver homogenates and were identified by their spectral properties and by comparison to synthetic standards as dihydrodiols, hydroxymethyl derivatives, and phenols; their relative levels of formation in liver homogenates from rats and mice were dependent on inducer pretreatment. In mouse skin in vivo, the major metabolite of 6-methyl-chrysene was trans-1,2-dihydro-1,2-dihydroxy-6-methylchrysene (6-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide. Its concentration was greater than that of trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed in mouse skin from 5-methylchrysene. Since 5-MeC-1,2-diol has been identified as a major proximate carcinogen of 5-methylchrysene, the further metabolism and tumorigenicity of 5-MeC-1,2-diol and 6-MeC-1,2-diol were compared. Both dihydrodiols were converted to 1,2,3,4-tetraols and to 1,2-dihydroxy metabolites to similar extents in mouse skin. However, 5-MeC-1,2-diol was significantly more active than was 6-MeC-1,2-diol as a tumor initiator on mouse skin. The formation of DNA adducts in mouse skin from 5-methylchrysene and 6-methylchrysene was compared. Both hydrocarbons gave qualitatively similar adduct patterns, but the formation of dihydrodiol epoxide type adducts was 1/20 as great from 6-methylchrysene as from 5-methylchrysene. The results of this study indicate that the weak tumorigenicity of 6-methylchrysene compared to that of 5-methylchrysene is not due to differing rates of formation or further metabolism of their 1,2-dihydrodiols but is a likely consequence of the lower activity of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene compared to 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; the unique structural feature of the latter is the presence of a methyl group and an epoxide ring in the same bay region.

Animals↗
PubMed1984

Dose-response study of the carcinogenicity of tobacco-specific N-nitrosamines in F344 rats.

Tobacco and tobacco smoke contain relatively high amounts of four tobacco-specific N-nitrosamines. Of these, N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N'-nitrosoanatabine (NAT) were bioassayed at three dose levels by subcutaneous injections into male and female F344 rats in 60 subdoses amounting in total to 9,3, and 1 mmol/kg. Compared with the solvent control group (trioctanoin), both NNN and NNK induced significant numbers of tumors of the nasal cavity (P less than 0.01) at all three dose levels in both male and female rats. Significant numbers of tumors were also induced by NNK in the lung at all three dose levels and in the liver at the highest dose level (P less than 0.05). In addition to nasal tumors NNN also induced esophageal tumors at a significant rate in male rats at the high and medium dose levels and in female rats at the high level (P less than 0.05); NAT was inactive at the three doses tested. Bioassays at lower dose levels as well as biochemical studies are strongly indicated for NNN and NNK since these nitrosamines occur in relatively high amounts in both chewing tobacco and tobacco smoke.

Animals↗
PubMed1984

Identification of ring oxidized metabolites of 1-nitropyrene in the feces and urine of germfree F344 rats.

1-Nitro[U-4,5,9,10-14C]pyrene in trioctanoin was administered by gavage to male germfree F344 rats. Extracts of the 120 h feces and urine were analyzed by h.p.l.c., with or without acetylation. 4,5-Dihydro-4,5-dihydroxy-1-nitropyrene, 1-nitro-3-hydroxypyrene, 1-nitro-6-hydroxypyrene and 1-nitro-8-hydroxypyrene but not 1-aminopyrene, 1-amino-6-hydroxypyrene or 1-amino-8-hydroxypyrene were identified by co-chromatography with standards. These results are in contrast to those obtained in the conventional F344 rat in which 1-aminopyrene, 1-amino-6-hydroxypyrene, and 1-amino-8-hydroxypyrene were fecal and urinary metabolites, indicating that intestinal microflora are involved in their formation.

Animals↗
PubMed1984

The bay-region geometry of some 5-methylchrysenes: steric effects in 5,6- and 5,12-dimethylchrysenes.

The presence of a bay-region methyl group in carcinogenic polycyclic aromatic hydrocarbons leads to considerable distortion in the molecule. This is illustrated in the structures, obtained by X-ray diffraction techniques, of 5,12- and 5,6-dimethylchrysene. The molecular distortions result from steric requirements, such as that the minimum H...H distance is 1.8 A and the minimum C...C distance is 2.90 A; distortions to accommodate these requirements may be both in-plane (by increasing the angles at carbon atoms in the bay-region from 120 degrees to approximately 124 degrees) and out-of-plane by torsion about certain bonds in the bay-region. It is shown that more in-plane distortions are found for 5-methylchrysene derivatives than for methylbenz[a]anthracene derivatives and this, it is suggested, results from the nature of the flexibility of the chrysene compared with the benz[a]anthracene fragment at the bay-region.

Carcinogens↗
PubMed1984

Tumorigenicity and metabolism of 1-nitropyrene in A/J mice.

Four groups of 28-32 male and female A/J mice were given i.p. injections of either trioctanoin or 1-nitropyrene in trioctanoin such that the total doses of 1-nitropyrene were 0.71 mmol/kg, 2.14 mmol/kg, or 6.44 mmol/kg. The mean number of lung tumors/mouse was 1.3 +/- 1.0 in the group treated with 6.44 mmol/kg of 1-nitropyrene compared with 0.3 +/- 0.6 in the trioctanoin group (p less than 0.001). Combined tumor incidence was not significant compared with controls in the two lower dose groups. Cultured explants of A/J mouse lung, and 9000 g supernatant of A/J mouse lung and liver, metabolized [14C]1-nitropyrene to 4,5-dihydro-4,5-dihydroxy-1-nitropyrene and 1-nitrohydroxypyrenes. Substantial amounts of unknown polar metabolites were also produced by cultured lung. Nitro-reduction to 1-aminopyrene was minimal in mouse lung and liver, even under oxygen deficient conditions.

Animals↗
PubMed1984

N-Nitroso-2-hydroxymorpholine, a mutagenic metabolite of N-nitrosodiethanolamine.

N-Nitroso-2-hydroxymorpholine was synthesized from N-(2-hydroxyethyl)aminoacetaldehyde diethylacetal by nitrosation and hydrolysis. It was detected as a metabolite of N-nitrosodiethanolamine in rat hepatic 9000 g supernatant. It was mutagenic toward Salmonella typhimurium TA 1535, with and without activation. The results suggest that N-nitroso-2-hydroxymorpholine, which is formed by metabolic beta-oxidation of N-nitrosodiethanolamine, could be involved in carcinogenesis by N-nitrosodiethanolamine.

Animals↗
PubMed1984

N-Nitroso(2-hydroxyethyl)glycine, a urinary metabolite of N,N-dinitrosopiperazine with potential utility as a monitor for its formation in vivo from piperazine.

Urinary metabolites in the rat of the carcinogen N,N-dinitrosopiperazine were identified as N-nitroso(2-hydroxyethyl)-glycine (22% of the dose), N-nitrosodiethanolamine (3%), 3-hydroxy-N-nitrosopyrrolidine (3%), and unchanged N,N-dinitrosopiperazine (18%). N-Nitroso(2-hydroxyethyl)glycine (1.6 mumol) was detected by gas chromatography-nitrosamine specific detection in the urine of rats treated by gavage with 19 mumol of piperazine and 191 mumol of sodium nitrite. Since sensitive methods are available to quantify N-nitroso(2-hydroxyethyl)glycine in rat urine and human urine, it has potential utility as a monitor for in vivo formation of N,N-dinitrosopiperazine.

Animals↗
PubMed1984

Formation of cyclic 1,N2-propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde.

Acrolein reacted with deoxyguanosine at pH 7 and 37 degrees to give three major products, Adducts 1 to 3, which were separated by high-performance liquid chromatography. They were identified by their ultraviolet, mass, and nuclear magnetic resonance spectra, by the spectra of the corresponding guanine derivatives, and by chemical transformations. Adducts 1 and 2 were two rapidly equilibrating diastereomers of 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-6- hydroxypyrimido [1,2-a]purine-10(3H)one, and Adduct 3 was 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8- hydroxypyrimido [1,2-a]purine-10(3H)one. Adducts 1 and 2 were formed by Michael addition of N-1 of deoxyguanosine to C-3 of acrolein, followed by ring closure between N2 of deoxyguanosine and C-1 of acrolein. Adduct 3 was formed by ring closure in the opposite direction. Adduct 3 was analogous to the major crotonaldehyde-deoxyguanosine adducts which were previously characterized. Adduct 3 (0.2 mmol/mol DNA-P) or the corresponding crotonaldehyde adduct (0.03 mmol/mol DNA-P) was formed when either acrolein or crotonaldehyde was allowed to react with DNA at pH 7 and 37 degrees. These results demonstrate that cyclic 1,N2-propanodeoxyguanosine adducts are formed by reaction of acrolein and crotonaldehyde with DNA.

Acrolein↗
PubMed1984

Identification of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene as a major mutagenic metabolite of 6-nitrochrysene.

Liver 9000 X g supernatant from rats was used to study the metabolism of [6- 14C]nitrochrysene under aerobic conditions. The major ethyl acetate-soluble metabolite (1.06 nmol/mg of protein in 30 min) was identified as 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, based on its mass, UV, and proton magnetic resonance spectra. Under aerobic conditions, 6-aminochrysene was not detected as a metabolite. However, when incubations were carried out in an atmosphere of 4% O2 in N2, both 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene (0.04 nmol/mg of protein) and 6-aminochrysene (0.05 nmol/mg of protein) were detected. Further metabolism of the 14C-labeled 1,2-dihydro-1,2-dihydroxy-6-nitrochrysene by rat liver 9000 X g supernatant under aerobic conditions gave a major metabolite which was identified tentatively as 1,2-dihydroxy-6-nitrochrysene. The mutagenic activities of 6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene were assessed in Salmonella typhimurium strains TA100 and TA98. In the absence of rat liver 9000 X g supernatant, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene was the more potent mutagen in TA100 but, in TA98, it was less active than was 6-nitrochrysene. In the presence of rat liver 9000 X g supernatant, both trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-nitrochrysene were more mutagenic in TA100 than in the assays performed without an activating system, and the dihydrodiol metabolite was more mutagenic than was 6-nitrochrysene. In TA98 with activation, trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, 6-aminochrysene, and 6-nitrochrysene were all mutagenic. The results of this study indicate that trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene is a major proximate mutagen of 6-nitrochrysene in S. typhimurium TA100.

Animals↗