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Biomedical subjects

Stephen S Hecht

Publications and source records attributed to Stephen S Hecht.

84 records · Page 5Linked to original sources
PubMed2002

Tobacco smoke carcinogens and breast cancer.

Cigarette smoking is an established cause of a variety of cancer types, but its role in breast cancer etiology is not clear. In this report, the potential role of cigarette smoke carcinogens as causes of human breast cancer is evaluated. Of over 60 known carcinogens in tobacco smoke, several are known to induce mammary tumors in laboratory animals: benzo[a]pyrene (B[a]P), dibenzo[a,l]pyrene (DB[a,l]P), 2-toluidine, 4-aminobiphenyl, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 1,3-butadiene, isoprene, nitromethane, ethylene oxide, and benzene. Studies in humans demonstrate that tobacco constituents can reach breast tissue. The uptake and metabolic activation of mammary carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and 4-aminobiphenyl are frequently higher in smokers than in nonsmokers. Although it is likely that specific mammary carcinogens in tobacco smoke can reach breast tissue, evidence is lacking at the present time. Some PAHs present in cigarette smoke can be metabolized to sterically hindered diol epoxides, which are potent mammary carcinogens. Thus, compounds such as benzo[c]phenanthrene (B[c]P), not classically considered to be a strong carcinogen in rodents, could nevertheless be metabolized in humans to diol epoxides carcinogenic to the breast. Collectively, the link between smoking and breast cancer is plausible but has been difficult to establish, probably because of the low carcinogen dose.

Animals↗
PubMed2002

Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention.

Much is now known about the carcinogens in cigarette smoke, their conversion to forms that react with DNA, and the miscoding properties of the resulting DNA adducts that cause the many genetic changes known to exist in human lung cancer. The chronic exposure of pulmonary DNA to a multitude of metabolically activated carcinogens is consistent with our current understanding of cancer as a disease resulting from many changes in key genes regulating growth. This review illustrates how this solid foundation of knowledge can be used to find new ways to prevent lung cancer. Three prevention-related topics are discussed: human uptake of tobacco carcinogens as a way of assessing risk and investigating mechanisms; individual differences in the metabolic activation and detoxification of carcinogens, which may relate to cancer susceptibility; and chemoprevention of lung cancer in smokers and ex-smokers. These new approaches are necessary as adjuncts to education and cessation efforts, which despite some success have not eliminated tobacco smoking.

Animals↗
PubMed2002

Analysis of N- and O-glucuronides of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in human urine.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific lung carcinogen which may play an important role as a cause of lung cancer in smokers. NNK is extensively metabolized to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which like NNK is a potent pulmonary carcinogen. NNAL in turn is glucuronidated, and both NNAL and its glucuronides are excreted in human urine. Previous studies have clearly demonstrated the presence in human urine of 4-(methylnitrosamino)-1-(3-pyridyl)-1-(O-beta-D-glucopyranuronosyl)butane (NNAL-O-Gluc), but did not exclude the presence of 4-(methylnitrosamino)-1-(3-pyridyl-N-beta-D-glucopyranuronosyl)-1-butanolonium inner salt (NNAL-N-Gluc). In this study, we quantified NNAL, NNAL-N-Gluc, and NNAL-O-Gluc in the urine of smokers, snuff-dippers, and people who used the oral tobacco product "toombak". The presence of NNAL-N-Gluc in the urine of toombak users was confirmed by LC-ESI-MS/MS. In smokers' urine, NNAL-N-Gluc, NNAL-O-Gluc, and NNAL comprised (mean +/- SD) 26.5 +/- 6.2, 32.1 +/- 17.6, and 41.4 +/- 16.6%, respectively, of total NNAL. In snuff-dippers' urine, the corresponding figures were 13.6 +/- 5.1, 46.6 +/- 11.7, and 36.6 +/- 9.3%. NNAL-N-Gluc comprised 50 +/- 25% of total glucuronidated NNAL in smokers and 24 +/- 12% in snuff-dippers. This difference was significant (P = 0.01), suggesting that smoking induces glucuronidation of NNAL. The results of this study demonstrate that NNAL-N-Gluc contributes substantially to NNAL-glucuronides in human urine. These results are important for a clearer understanding of mechanisms of detoxification of NNK in humans.

Carcinogens↗
PubMed2002

Disposition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in bile duct-cannulated rats: stereoselective metabolism and tissue distribution.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a chiral compound, and the primary metabolite of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major carcinogen in tobacco smoke. The goal of the present work was to study the pharmacokinetics and stereoselective metabolism and tissue retention of NNK and NNAL in the rat. Groups of rats were dosed with [5-(3)H]NNK (n = 3) or racemic [5-(3)H]NNAL (n = 3) at a target dose of 8.45 micromol/kg and were killed at selected time points for tissue collection. Separate groups of rats (n =5 per group) received the same dose of either NNK or NNAL and serial sampling of blood, bile and urine was carried out over 24 h. All samples were analyzed by C(18) reversed-phase HPLC with gradient elution and radioflow detection. A gas chromatograph-thermal energy analyzer (GC-TEA) was used to separate the (R)-/(S)-NNAL enantiomers. Racemic NNAL and NNK had large volumes of distribution (321 +/- 137 ml for NNK and 2772 +/- 1423 ml for NNAL) and similar total body clearances (12.8 +/- 2.0 ml/min for NNK and 8.6 +/- 2.6 ml/min for NNAL). The results indicated that the enantiomers of NNAL are stereoselectively metabolized and excreted. The glucuronide of (R)-NNAL, ((R)-NNAL-Gluc) was identified as the major metabolite in the bile after administration of either NNK or NNAL. (R)-NNAL was the major NNAL enantiomer in the bile or urine samples. At 24 h after racemic NNAL administration, NNAL comprised an average of 75.4% of total radioactivity in the lung with an (S)-/(R)-ratio of >20. The stereoselective localization of (S)-NNAL to lung tissue may contribute to the lung selectivity of NNK carcinogenesis. The present studies suggest a need to look beyond metabolic activation as the sole mechanism for lung carcinogenesis.

Animals↗
PubMed2002

Ethylation and methylation of hemoglobin in smokers and non-smokers.

Two previous studies demonstrated elevated levels of 3-ethyladenine in smokers' urine, suggesting that cigarette smoke may contain a DNA ethylating agent. We hypothesized that such an agent would also lead to elevated levels of N-terminal N-ethylvaline in hemoglobin. N-terminal N-alkylated valines in hemoglobin can be measured using a modified Edman degradation, which employs pentafluorophenyl isothiocyanate to produce a pentafluorophenylthiohydantoin. The latter is quantified by gas chromatography-negative ion chemical ionization-mass spectrometry (GC-NICI-MS). We modified the published method to increase its sensitivity and selectivity, thereby allowing quantification of N-terminal N-ethylvaline. Modifications included the use of a deuterated peptide as the internal standard, the introduction of an HPLC purification step, and the use of tandem mass spectrometry (MS/MS) for detection and quantification of the analyte, 1-ethyl-5-isopropyl-3-pentafluorophenyl-2-thiohydantoin. We also quantified N-terminal N-methylvaline in the same samples. The mean level of N-terminal N-ethylvaline in the hemoglobin of smokers was 3.76 +/- 2.77 pmol/g globin (n = 39), significantly higher than in non-smokers, 2.50 +/- 1.65 pmol/g globin (n = 28), P = 0.023. The difference remained significant after correction for gender and age. The mean level of N-terminal N-methylvaline in smokers was 997 +/- 203 pmol/g globin (n = 45) compared with 904 +/- 149 pmol/g globin in non-smokers (n = 29); these values were not significantly different when corrected for gender and age. As levels of hemoglobin and DNA adducts often correlate, the results of this study support the proposal that cigarette smoke contains an as yet unidentified ethylating agent, which might be involved in DNA damage and tumor initiation.

Alkylating Agents↗
PubMed2002

Human urinary carcinogen metabolites: biomarkers for investigating tobacco and cancer.

Measurement of human urinary carcinogen metabolites is a practical approach for obtaining important information about tobacco and cancer. This review presents currently available methods and evaluates their utility. Carcinogens and their metabolites and related compounds that have been quantified in the urine of smokers or non-smokers exposed to environmental tobacco smoke (ETS) include trans,trans-muconic acid (tt-MA) and S-phenylmercapturic acid (metabolites of benzene), 1- and 2-naphthol, hydroxyphenanthrenes and phenanthrene dihydrodiols, 1-hydroxypyrene (1-HOP), metabolites of benzo[a]pyrene, aromatic amines and heterocyclic aromatic amines, N-nitrosoproline, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (NNAL and NNAL-Gluc), 8-oxodeoxyguanosine, thioethers, mercapturic acids, and alkyladenines. Nitrosamines and their metabolites have also been quantified in the urine of smokeless tobacco users. The utility of these assays to provide information about carcinogen dose, delineation of exposed vs. non-exposed individuals, and carcinogen metabolism in humans is discussed. NNAL and NNAL-Gluc are exceptionally useful biomarkers because they are derived from a carcinogen- 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)- that is specific to tobacco products. The NNAL assay has high sensitivity and specificity, which are particularly important for studies on ETS exposure. Other useful assays that have been widely applied involve quantitation of 1-HOP and tt-MA. Urinary carcinogen metabolite biomarkers will be critical components of future studies on tobacco and human cancer, particularly with respect to new tobacco products and strategies for harm reduction, the role of metabolic polymorphisms in cancer, and further evaluation of human carcinogen exposure from ETS.

Biomarkers↗
PubMed2002

Effects of benzyl isothiocyanate and phenethyl isothiocyanate on DNA adduct formation by a mixture of benzo[a]pyrene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung.

Dietary phenethyl isothiocyanate (PEITC) and a mixture of dietary PEITC and benzyl isothiocyanate (BITC) inhibit lung tumorigenesis in A/J mice induced by a mixture of the tobacco smoke carcinogens benzo[a]pyrene (B[a]P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In this study, we tested the hypothesis that inhibition of tumorigenesis by these isothiocyanates was due to inhibition of DNA adduct formation. We quantified the following pulmonary DNA adducts: N2-[7,8,9-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene-10-yl]deoxyguanosine (BPDE-N2-dG) from B[a]P; and O(6)-methylguanine (O(6)-mG) and 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing adducts from NNK. Initial experiments demonstrated that there were no effects of B[a]P on NNK-DNA adduct formation, or vice versa, and established by way of a time course study the appropriate sacrifice intervals for the main experiment. Dietary PEITC, or dietary BITC plus PEITC, inhibited the formation of HPB-releasing DNA adducts of NNK at several of the time points examined. There were no effects of dietary isothiocyanates on levels of O(6)-mG or BPDE-N2-dG. These results, which are consistent with previous studies in rats and with tumor inhibition data in mice, support a role for inhibition of HPB-releasing DNA adducts of NNK as a mechanism of inhibition of tumorigenesis by dietary PEITC and BITC plus PEITC. However, the observed inhibition was modest, suggesting that other effects of isothiocyanates are also involved in chemoprevention in this model.

Animals↗
PubMed2002

Inhibition of lung tumorigenesis in A/J mice by N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine and myo-inositol, individually and in combination.

Isothiocyanates, their N-acetylcysteine conjugates, and myo-inositol (MI) are inhibitors of lung tumorigenesis in A/J mice. However, chemoprevention by combinations of these compounds in different temporal sequences has not been examined. This is important for developing practical approaches to lung cancer chemoprevention in smokers and ex-smokers. We used a tumor model in which A/J mice are treated with 8 weekly doses of benzo[a]pyrene (B[a]P) plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and killed 19 weeks after the final treatment. In Experiment 1, isothiocyanates or their N-acetylcysteine conjugates were added to the diet (1 or 3 micro mol/g) from 1 week before until 1 week after carcinogen treatment. The compounds were 2-phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), N-acetyl-S-(N-benzyl-thiocarbamoyl)-L-cysteine (BITC-NAC), N-acetyl-S-(N-2-phenethylthiocarbamoyl)-L-cysteine (PEITC-NAC), and N-acetyl-S-(N-3-phenylpropylthiocarbamoyl)-L-cysteine (PPITC-NAC). Significant reductions in lung tumor multiplicity were observed in mice treated with PEITC, PEITC-NAC, PPITC and PPITC-NAC. PEITC-NAC was chosen for combination studies with MI (Experiment 2). Mice were treated with B[a]P plus NNK without or with PEITC-NAC (3 micro mol/g diet), MI (55.5 micro mol/g diet), or PEITC-NAC plus MI (3 micro mol plus 55.5 micro mol/g diet). Different temporal sequences of dietary additions were investigated: carcinogen treatment phase; post-carcinogen treatment phase; entire experiment; 50% of carcinogen treatment phase until termination; and 75% of carcinogen treatment phase until termination. All treatments reduced lung tumor multiplicity except PEITC-NAC post-carcinogen or from 75% of the carcinogen treatment phase. Reduction of lung tumor multiplicity by PEITC-NAC plus MI was greater than that in the mice treated with the agents alone in all temporal sequences. When all results were combined, PEITC-NAC plus MI was significantly more effective than the agents alone. There was a significant trend for reduction in lung tumor multiplicity with increased duration of treatment by the chemopreventive agents. These results provide a basis for further development of mixtures of PEITC-NAC and MI for chemoprevention of lung cancer.

Animals↗
PubMed2002

Metabolism and pharmacokinetics of N'-nitrosonornicotine in the patas monkey.

N'-Nitrosonornicotine (NNN) is present in significant quantities in tobacco and tobacco smoke and is believed to play an important role as a cause of cancer in people who use tobacco products. Biomarkers of NNN uptake in humans such as urinary metabolites would be useful for assessing cancer risk. Previous studies, carried out almost exclusively in rodents, have characterized urinary metabolites of NNN, but none of these would be suitable as a biomarkers of NNN uptake in humans. Therefore, we studied NNN metabolism in the patas monkey. Monkeys were treated intravenously with [5-(3)H]NNN, which has tritium in the pyridine ring. Blood and urine samples were collected at timed intervals. Six urinary metabolites were observed by high-performance liquid chromatography (HPLC) and were identified by their spectral properties and/or comparison to appropriate standards as follows: metabolite (% of radioactivity eluting from HPLC +/- S.D., n = 3 monkeys); 4-hydroxy-4-(3-pyridyl)butyric acid (43.8 +/- 4.0); 4-oxo-4-(3-pyridyl) butyric acid (2.7 +/- 0.66); norcotinine (13.1 +/- 2.7); norcotinine-1N-oxide (16.5 +/- 1.3); 3'-hydroxynorcotinine (16.9 +/- 2.0); 3'-(O-beta-D-glucopyranuronosyl)hydroxynorcotinine (5.4 +/- 1.0); and unchanged NNN (0.63 +/- 0.15). The two major metabolites in serum were 4-hydroxy-4-(3-pyridyl)butyric acid and norcotinine. NNN was rapidly metabolized to 4-hydroxy-4-(3-pyridyl)butyric acid, whereas the formation of norcotinine and 3'-hydroxynorcotinine were somewhat delayed. The results of this study demonstrate substantial differences between NNN metabolism in the rodent and patas monkey. Metabolism of NNN to norcotinine and its derivatives was far more prevalent in the patas monkey than in the rat. 3'-Hydroxynorcotinine and its O-glucuronide may be formed from NNN via alpha-oximinonornicotine or isomyosmine. There was no evidence that it was formed via norcotinine, although this pathway could not be excluded. 3'-Hydroxynorcotinine could potentially be a biomarker of NNN uptake in humans.

Animals↗
PubMed2002

Relationship of exposure to coke-oven emissions and urinary metabolites of benzo(a)pyrene and pyrene in coke-oven workers.

Coke-oven workers are occupationally exposed to a high concentration of polycyclic aromatic hydrocarbons (PAH). r-7,t-8,9,c-10-Tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (trans-anti-BaP-tetraol) and 1-hydroxypyrene (1-OHP) are urinary metabolites of benzo(a)pyrene and pyrene, respectively. In this study, we investigated the relationship among individual air exposure to benzene soluble fraction (BSF) of total particulates, as a surrogate marker of ambient PAH exposures, and urinary trans-anti-BaP-tetraol and 1-OHP concentrations in coke-oven workers at a steel plant in Taiwan. Fifty-seven subjects, including 41 male workers who work in one coke-oven plant and 16 men (referents) from an administrative area, were studied. The mean trans-anti-BaP-tetraol and 1-OHP concentrations (mean +/- SD) were 0.4 +/- 0.3 nmol/mol creatinine and 9.7 +/- 21.6 micromol/mol creatinine, respectively, in coke-oven workers. These levels were significantly higher than those in referents (0.03 +/- 0.03 nmol/mole creatinine, P < 0.001 and 0.4 +/- 0.2 micromol/mol creatinine, P < 0.01, respectively). Urinary trans-anti-BaP-tetraol concentrations were significantly and positively correlated with individual average BSF and urinary 1-OHP concentrations. That is, the higher the urinary trans-anti-BaP-tetraol concentrations, the more ambient BSF exposure and urinary 1-OHP concentrations (Spearman correlation coefficients r = 0.68 and 0.70, respectively; P < 0.0001; n = 57). These findings suggest that urinary 1-OHP and trans-anti-BaP-tetraol might be considered as potential biomarkers for the assessment of uptake of known PAH carcinogens in the air.

Adult↗