Biomedical subjects

S S Hecht

Publications and source records attributed to S S Hecht.

At least 217 records · Page 12Linked to original sources

PubMed1986

Effects of the co-carcinogen catechol on benzo[a]pyrene metabolism and DNA adduct formation in mouse skin.

We have studied the effects of the co-carcinogen catechol (1,2-dihydroxybenzene) on the metabolic activation of [3H] benzo[a]pyrene (BaP) in mouse skin, in vivo and on the binding of BaP metabolites to DNA and protein at intervals from 0.5-24 h. Upon topical application of 0.015 mg [3H]BaP and 0.25 or 0.5 mg catechol per mouse, catechol had little effect on the total amount of [3H]BaP metabolized in mouse skin, but it affected the relative proportions of [3H]BaP metabolites. Catechol (0.5 mg/mouse) decreased the proportion of water-soluble [3H]BaP metabolites, ethyl acetate-soluble polar metabolites and quinones, but doubled the levels of unconjugated 3-hydroxy-BaP at all measured intervals after treatment. Catechol also caused a small increase in the levels of trans-7,8-dihydroxy-7,8-dihydroBaP and trans-9,10-dihydroxy-9,10-dihydroBaP 0.5 h after treatment. Two hours after treatment, the levels of these metabolites subsided to those of the controls. Catechol did not affect the levels of glutathione conjugates of BaP. However, it caused a decrease in glucuronide and sulphate conjugate formation from BaP. Catechol caused an approximately 2-fold increase in the formation of anti-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydroBaP (BPDE) DNA adducts and elevated the ratio of anti-syn-BPDE-DNA adducts 1.6 to 2.9-fold. Catechol treatment increased the radioactivity associated with epidermal proteins after [3H]BaP application. Because catechol increased levels of 3-hydroxyBaP, we considered the possibility that 3-hydroxyBaP might enhance the tumor initiating activities of BaP or BPDE in mouse skin; a bioassay demonstrated that this was not the case. The results of this study indicate that one important effect of catechol related to its co-carcinogenicity is its ability to enhance formation of anti-BPDE-DNA adducts in mouse skin.

Animals↗

PubMed1986

Synthesis of 6-methylchrysene-1,2-diol-3,4-epoxides and comparison of their mutagenicity to 5-methylchrysene-1,2-diol-3,4-epoxides.

The syn- and anti-isomers of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene (6-MeC-1,2-diol-3,4-epoxide) were synthesized and their mutagenic activities in Salmonella typhimurium were compared with those of the syn- and anti-isomers of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (5-MeC-1,2-diol-3,4-epoxide). The most mutagenic compound was anti-5-MeC-1,2-diol-3,4-epoxide, followed by syn-5-MeC-1,2-diol-3,4-epoxide. At the same doses, neither of the 6-MeC-1,2-diol-3,4-epoxides was mutagenic. These results demonstrate the enhancing effect on mutagenicity of a methyl group in the same bay region as the epoxide ring of a diol epoxide.

Carcinogens↗

PubMed1986

Comparative mutagenicity of 4-(carbethoxynitrosamino)-4-(3-pyridyl)butanal and 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone, model compounds for alpha-hydroxylation of N'-nitrosonornicotine.

4-(Carbethoxynitrosamino)-1-(3-pyridyl)butanal, a stable precursor to the putative diazohydroxide formed by 5'-hydroxylation of the tobacco-specific nitrosamine, N'-nitrosonornicotine, was synthesized in six steps from nicotinaldehyde. Its mutagenicity toward S. typhimurium was compared to that of 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone, a precursor to the diazohydroxide formed by 2'-hydroxylation of N'-nitrosonornicotine. At equimolar doses, 4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone was a potent mutagen, but 4-(carbethoxynitrosamino)-1-(3-pyridyl)butanal was inactive toward strains TA 100 and TA 1535. The results of this study indicate that the putative diazohydroxide formed by 2'-hydroxylation of N'-nitrosonornicotine has higher inherent mutagenicity toward S. typhimurium than does the corresponding diazohydroxide formed by 5'-hydroxylation.

Magnetic Resonance Spectroscopy↗

PubMed1986

Effects of 6-nitro substitution on 5-methylchrysene tumorigenicity, mutagenicity and metabolism.

6-Nitro-5-methylchrysene was prepared by nitration of 5-methylchrysene and the mutagenic and tumorigenic activities of the two compounds were compared. Whereas 5-methylchrysene was a strong tumor initiator on mouse skin, no tumors were observed in the mice treated with 6-nitro-5-methylchrysene. In Salmonella typhimurium TA100, both compounds were mutagenic in the presence, but not in the absence, of rat liver 9000 g supernatant. The major metabolite of 6-nitro-5-methylchrysene in rat liver in vitro was trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene. In view of the ready conversion of 6-nitro-5-methylchrysene to a 1,2-dihydrodiol, its apparent lack of tumorigenicity in mouse skin was intriguing.

Animals↗

PubMed1986

Synthesis of K-region derivatives of the carcinogen 1-nitropyrene.

The synthesis of potential metabolites of 1-nitropyrene, resulting from oxidation at the K-regions, is described. Reaction of 1-nitropyrene with OsO4 gave the cis-4,5- and 9,10-dihydrodiols. These were separated and oxidized with activated MnO2 to give the corresponding 4,5- and 9,10-diones; further oxidation to the highly mutagenic lactones, 1- and 3-nitro-5H-phenanthro[4,5-bcd]pyran-5-one, was observed in these reactions. Reduction of the 4,5-dione with KBH4 gave the trans-4,5-dihydrodiol, which was identical to one of the metabolites of 1-nitropyrene. Reduction of the 9,10-dione gave an unstable trans-9,10-dihydrodiol, which was characterized as its diacetate. The u.v. spectra, n.m.r. spectra and h.p.l.c. retention times of these compounds are presented.

Carcinogens↗

PubMed1986

Induction of liver tumors in F344 rats by crotonaldehyde.

The tumorigenic activities in F344 rats of crotonaldehyde, a representative alpha, beta-unsaturated carbonyl compound, and N-nitrosopyrrolidine, which could produce crotonaldehyde upon metabolism, were compared. Groups of rats were treated with either crotonaldehyde (0.6 mM or 6.0 mM) or N-nitrosopyrrolidine (0.6 mM) in their drinking water for 113 or 84 weeks, respectively. At the 0.6 mM dose, crotonaldehyde induced neoplastic lesions of the liver in 9 of 27 rats; 2 rats had hepatocellular carcinomas, and 9 rats had neoplastic nodules. It also caused altered liver cell foci in 23 of 27 rats. The incidences of tumors and foci were significantly higher than those of the control group. N-Nitrosopyrrolidine induced hepatocellular carcinomas in 20 of 23 rats, liver neoplastic nodules in 16 of 23 rats, and altered liver cell foci in 23 of 23 rats. Thus, crotonaldehyde appears to be a weaker tumorigen than N-nitrosopyrrolidine. At the 6.0 mM dose, crotonaldehyde treatment caused moderate to severe liver damage in 10 of 23 rats. No preneoplastic or neoplastic lesions were observed in these rats. The remaining 13 rats of this group developed altered liver cell foci. The tumorigenicity of crotonaldehyde suggests that alpha, beta-unsaturated carbonyl compounds, which are ubiquitous in the human environment and can be formed endogenously, may be an important class of potential carcinogens.

Adenoma, Bile Duct↗

PubMed1986

Induction of oral cavity tumors in F344 rats by tobacco-specific nitrosamines and snuff.

The tumorigenic activities toward the oral cavity of snuff, its extracts, and two of its major nitrosamines, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were evaluated in male F344 rats. In one protocol, groups of 21-30 rats were treated beginning at age 10 weeks by chronic application to the oral cavity for 131 weeks of either H2O, an H2O extract of snuff, an H2O extract of snuff enriched with ten times its indigenous concentration of NNN and NNK, or with NNN and NNK in H2O. The incidence of oral cavity tumors in the rats treated with NNN and NNK was 8 of 30, compared to 0 of 30 in controls (P less than 0.05). These results demonstrate that NNN and NNK can induce tumors locally in the oral cavity of F344 rats. Oral cavity tumors were also observed in 3 of 30 rats treated with snuff extract enriched with NNN and NNK, but not in the rats treated with snuff extract alone. In a second protocol, a test canal was surgically created in the lower lip of groups of 21-32 rats, and either snuff, H2O-extracted snuff, or snuff enriched with its own H2O extract was inserted in the test canal 5 times weekly for 116 weeks. A group of 10 control rats had surgery only. Among the 32 rats treated with snuff, 3 had oral cavity tumors; one was a squamous cell carcinoma originating in the test canal and invading the gingiva, one was a papilloma of the test canal, and one was a papilloma of the hard palate. Oral cavity tumors were also observed in 2 of 21 rats treated with H2O-extracted snuff and 1 of 32 rats treated with snuff enriched with its H2O extract. Oral tumors were not observed in control rats. The results of this study indicate that snuff and individual nitrosamines present in snuff can induce oral cavity tumors in F344 rats and support the epidemiological observations which indicate that snuff dipping causes oral cancer in man.

Animals↗

PubMed1986

Identification and quantitative determination of aniline and toluidines in human urine.

Aniline and o-, m-, and p-toluidine, which are representative of aromatic amines in cigarette smoke, were identified and quantified in human urine. Smokers excreted 3.1 +/- 2.6 micrograms/24 h of aniline and 6.3 +/- 3.7 micrograms/24 h of o-toluidine (n = 16). Nonsmokers excreted 2.8 +/- 2.5 micrograms/24 h of aniline and 4.1 +/- 3.2 micrograms/24 h of o-toluidine (n = 12). Meta- and p-toluidine were detected in the urine of 2 of 11 smokers and 4 of 9 nonsmokers. The observed intra- and interindividual variations in the amounts of urinary aniline and o-toluidine were relatively large. The results of this study demonstrate for the first time that aniline and toluidines are present in human urine and suggest that sources other than cigarette smoke contribute significantly to their concentrations in urine.

Adult↗

PubMed1986

Formation of cyclic nucleic acid adducts from some simple alpha, beta-unsaturated carbonyl compounds and cyclic nitrosamines.

To determine the structures of the DNA adducts of two cyclic nitrosamines, N-nitrosopyrrolidine and N-nitrosomorpholine, the model compounds, alpha-acetoxy-N-nitrosopyrrolidine, 4-(carbethoxynitrosamino)butanal and 2-(carbethoxynitrosamino)ethoxyacetaldehyde, were allowed to react with deoxyguanosine in the presence of porcine liver esterase or base. These model compounds are stable precursors of intermediates formed upon metabolic alpha-hydroxylation of N-nitrosopyrrolidine and N-nitrosomorpholine. The major adducts formed in these reactions were isolated and characterized, on the basis of ultraviolet absorption, mass spectrometry, proton nuclear magnetic resonance and chromatographic properties, as structurally unique 1,N2-cyclic deoxyguanosine adducts. Reaction of crotonaldehyde and glyoxal with deoxyguanosine at 37 degrees C, pH 7, also led to the formation of 1,N2-cyclic deoxyguanosine adducts identical to those formed from the model compounds for alpha-hydroxylation of N-nitrosopyrrolidine and N-nitrosomorpholine, respectively. The 1,N2-cyclic deoxyguanosine adducts were also formed in DNA, upon incubation with N-nitrosopyrrolidine and rat liver microsomes. Acrolein, the simplest alpha, beta-unsaturated carbonyl compound, reacted readily with deoxyguanosine to form three major adducts. These adducts were characterized as cyclic 1,N2-propanodeoxyguanosine adducts resulting from Michael addition of acrolein to the 1- and N2-positions of deoxyguanosine followed by ring closure. One of these adducts, as well as the corresponding crotonaldehyde adduct, was formed in calf thymus DNA upon reaction with acrolein or crotonaldehyde under physiological conditions. The level of modification of DNA by acrolein was considerably higher than that by either crotonaldehyde or N-nitrosopyrrolidine.

Acetaldehyde↗

PubMed1986

Effects of chronic ethanol consumption on benzo(a)pyrene metabolism and glutathione S-transferase activities in Syrian golden hamster cheek pouch and liver.

The metabolism of benzo(a)pyrene (BaP) by hepatic or cheek pouch epithelium microsomes obtained from Syrian golden hamsters which had been consuming an ethanol-containing liquid diet for 4 wk and from pair-fed controls was measured. Glutathione S-transferase activity with 1-chloro-2,4-dinitrobenzene or (+/-)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene as substrates was measured in cytosol obtained from the liver or cheek pouch epithelium of the same animals. Cytosolic hepatic glutathione levels were measured in both ethanol-consuming and control animals. The metabolism of BaP to 4,5-dihydro-4,5-dihydroxybenzo(a)pyrene (BaP-4,5-diol), 7,8-dihydro-7,8-dihydroxybenzo(a)pyrene (BaP-7,8-diol), 9-hydroxybenzo(a)pyrene (9-OH-BaP), and 3-hydroxybenzo(a)pyrene (3-OH-BaP) by hepatic microsomes from ethanol-consuming hamsters was significantly reduced (40-52%) (P less than 0.05) compared to control microsomes. However, a 2-fold increase (P less than 0.05) in the metabolism of BaP to BaP-7,8-diol and 9,10-dihydro-9,10-dihydroxybenzo(a)pyrene was measured with microsomes from the cheek pouch epithelium of ethanol-consuming animals. There was no significant change in the production of BaP-4,5-diol, 9-OH-BaP, or 3-OH-BaP by cheek pouch epithelium microsomes of ethanol-consuming hamsters compared to controls. No difference in glutathione S-transferase activity of hepatic or cheek pouch epithelium cytosol between control and ethanol-consuming hamsters towards 1-chloro-2,4-dinitrobenzene or (+/-)-r-7,t-8-dihydroxy-t-9,10- epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene was observed. Hepatic glutathione content was significantly (P less than 0.05) decreased after 2 wk (23%) and 4 wk (33%) of ethanol consumption. The results suggest a mechanism by which ethanol might enhance BaP tumorigenesis in the hamster cheek pouch.

Alcoholism↗

PubMed1986

Effects of butylated hydroxyanisole on the tumorigenicity and metabolism of N-nitrosodimethylamine and N-nitrosopyrrolidine in A/J mice.

Female A/J mice were maintained on NIH-07 diet or on NIH-07 diet containing butylated hydroxyanisole (BHA, a mixture of 2- and 3-tert-butyl-4-hydroxyanisole), 5 mg/g, for 1 week prior to and during 10 weeks of treatment with N-nitrosodimethylamine (NDMA) or N-nitrosopyrrolidine (NPYR), administered in the drinking water. Twenty weeks after nitrosamine treatment ended, mice were sacrificed and lung adenomas were counted. BHA inhibited NDMA tumorigenesis but enhanced NPYR tumorigenesis. Treatment of A/J mice for three weeks with BHA (5 mg/g) added to semisynthetic diet increased whole lung microsomal alpha-hydroxylation of NDMA and NPYR, as measured by aldehyde production, and increased lung and hepatic glutathione-S-transferase activities. No evidence was found for formation of S-methylglutathione in incubations with NDMA and hepatic supernatants obtained from BHA treated or control mice. Four h after gavage of NDMA, levels of 7-methylguanine in the lung DNA of mice treated with BHA were higher than in the lung DNA of control mice, but levels of O6-methylguanine in the two groups were the same. The results of this study indicate that BHA treatment increases the microsomal metabolic alpha hydroxylation of both NDMA and NPYR, but has differential effects on their tumorigenic activities.

Animals↗

PubMed1986

Comparative tumorigenicity and DNA methylation in F344 rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N-nitrosodimethylamine.

The tumorigenic activities and DNA methylating abilities in F344 rats of the tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and the structurally related nitrosamine N-nitrosodimethylamine (NDMA) were compared. Groups of 30 male rats were given 60 s.c. injections of 0.0055 mmol/kg of either NNK or NDMA over a 20-week period (total dose, 0.33 mmol/kg). The experiment was terminated after 104 weeks. The numbers of rats with tumors were as follows for NNK and NDMA, respectively: liver, 10 and 6; lung 13 and 0; and nasal cavity, 6 and 1. NNK was significantly more tumorigenic than was NDMA toward the lung (P less than 0.01) and nasal cavity (P less than 0.05). Groups of rats were treated with a single s.c. injection of 0.39 mmol/kg or 0.055 mmol/kg of NNK or NDMA and the levels of 7-methylguanine and O6-methylguanine were measured in liver, lung, and nasal mucosa 1-48 h after treatment. In liver and lung, levels of 7-methylguanine and O6-methylguanine in DNA were 3-22 times (P less than 0.001) greater in NDMA treated rats than in NNK treated rats. Levels of methylation induced by NDMA and NNK in the nasal mucosa were similar. The results of this study demonstrate that NNK is a more potent tumorigen than NDMA in the F344 rat and suggest that DNA methylation alone does not account for its strong tumorigenicity in rat lung and nasal mucosa.

Animals↗

PubMed1985

Dual-label high-performance liquid chromatographic assay for femtomole levels of benzo[a]pyrene metabolites.

A dual-label HPLC assay to measure femtomole quantities of ethyl acetate-extractable [3H]benzo[a]pyrene metabolites was developed. 14C-labeled metabolites of benzo[a]pyrene formed by rat liver 9000g supernatant were used as both internal standards and chromatographic markers. The percentage deviation between assays was determined to be between 11 and 13% for 9,10-dihydro-9,10-dihydroxybenzo[a]pyrene, 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene, benzo[a]pyrene-3,6-quinone, benzo[a]pyrene-1,6-quinone, and 9-hydroxybenzo[a]pyrene, 22% for 4,5-dihydro-4,5-dihydroxybenzo[a]pyrene, and less than 5% for 3-hydroxybenzo[a]pyrene. The detection limit of this assay was between 3 and 10 fmol per metabolite. The application of this technique to the metabolism of [3H]benzo[a]pyrene by microsomes of hamster and human oral cavity tissue is described.

Animals↗

PubMed1985

High-performance liquid chromatographic analysis of metabolites of the nicotine-derived nitrosamines, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

An improved high-performance liquid chromatographic system was developed for separation of 11 metabolites of the nicotine-derived nitrosamines N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The new system employed a 5-microns octadecylsilane bonded column eluted with aqueous sodium acetate-methanol gradients of varying pH. Analysis times were typically 30 min for NNN metabolites and 50 min for NNK metabolites, compared to 80 and 90 min, respectively, when 10-microns columns were used. The E and Z isomers of all nitrosamine-containing metabolites of NNK were separated. The chromatographic behavior of the 11 metabolites as well as NNN and NNK was studied between pH 4.0 and 7.5. The retention times of several metabolites were altered significantly as a function of pH. The results of the pH study provide valuable additional criteria for metabolite identification as well as optimized conditions for their separation. Applications of the system to the metabolism of [2'-14C]NNN in cultured rat esophagus and [carbonyl-14C]NNK in rat liver slices are presented.

Animals↗

PubMed1985

Analysis of syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene -deoxyribonucleoside adducts by boronate chromatography.

The Servacel DHB (m-dihydroxyborylphenylaminoethyl cellulose) chromatographic procedure developed by Sawiki et al. (Cancer Res., 43,3212-3218, 1983) for analysis of 7,12-dimethylbenz[a]anthracene (DMBA)-DNA adducts was applied to analyze syn- and anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (DE-I)-deoxyribonucleoside adducts. Identical elution conditions to whose developed for the DMBA adducts were employed. While the results were similar to those obtained in the DMBA system, some of the anti-DE-I-deoxyribonucleoside adducts eluted with the buffer system used for elution of syn-adducts. Complete resolution of the anti- and syn-adducts was obtained when modified elution conditions as developed by Pruess-Schwartz et al. (Cancer Res., 44, 4104-4110, 1984) for analysis of syn- and anti-7 alpha-8 beta-dihydroxy-9 beta, 10 beta-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene--DNA adducts were applied. Based on this chromatographic procedure about 15% of the DE-I-deoxyribonucleoside adducts, formed in mouse skin DNA upon treatment with 5-[3H]methylchrysene (MeC), originated from syn-DE-I.

Animals↗

PubMed1985

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

The mutagenic activities toward Salmonella typhimurium TA100 and tumor initiating activities on mouse skin of the polynuclear aromatic hydrocarbons benzo[k]fluoranthene (BkF),2-methylBkF,8-methylBkF,9-methyl-BkF and 7,12-dimethylBkF were compared. BkF and 2-methylBkF were the most mutagenic of the compounds tested and had comparable activity; they were more active than 7,12-dimethylBkF. 8-MethylBkF and 9-methylBkF were not mutagenic. BkF and the methylated BkFs had similar tumor initiating activities on mouse skin. The results suggest that 8,9-dihydro-8,9-epoxy-BkF might be involved in the metabolic activation of BkF to a mutagen, but do not indicate which metabolite may be involved in BkF tumorigenesis.

Animals↗

PubMed1985

Nicotine: a precursor for carcinogens.

Eric Boyland and collaborator demonstrated about 20 years ago that N'-nitrosonornicotine (NNN), a suspected smoke constituent, was a lung carcinogen in mice and that thiocyanate, a major detoxification product of the smoke component hydrogen cyanide, catalyzes the endogenous formation of nitrosamines. Also, Boyland presumed that the enzymatic conversion of nicotine may contribute to the carcinogenic potential of cigarette smoke via reactive intermediates. Chemical, biochemical and bioassay data gathered since these first observations, support the concept that the nicotine-derived NNN and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) contribute significantly to the carcinogenic activity of snuff and cigarette smoke. Reactive metabolites of nicotine may also be carcinogenic factors. This hypothesis requires exploration.

Animals↗

PubMed1985

Formation of the cyclic 1,N2-glyoxal-deoxyguanosine adduct upon reaction of N-nitroso-2-hydroxymorpholine with deoxyguanosine.

N-nitroso-2-hydroxymorpholine, a mutagenic metabolite of N-nitrosomorpholine and N-nitrosodiethanolamine, reacted with deoxyguanosine at pH 7, 37 degrees C, to give 3-(2-deoxy-beta-D-erythropentofuranosyl)-6,7-dihydro-6,7-dihydr oxyimidazo- [1,2-a]purine-9(3H)one, which is also formed by reaction of deoxyguanosine with glyoxal. The results suggest that this adduct might be involved in DNA binding by N-nitrosomorpholine and N-nitrosodiethanolamine.

Chemical Phenomena↗