Biomedical subjects

S S Hecht

Publications and source records attributed to S S Hecht.

At least 199 records · Page 11Linked to original sources

PubMed1988

Synthesis and mutagenicity of 5-alkyl-substituted chrysene-1,2-diol-3,4-epoxides.

In order to explore the relationship between structure and mutagenicity of bay region diol-epoxides of chrysene substituted with an alkyl group in the bay region, we compared the mutagenicity in Salmonella typhimurium TA 100 of anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene with its 5-methyl, 5-ethyl and 5-propyl derivatives. The results showed that anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (7400 revertants/nmol) was the most mutagenic of these diol-epoxides followed by anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene and its 5-ethyl derivative (1100 revertants/nmol). The 5-propyl substituted diol-epoxide was inactive at the doses tested. The results demonstrate that steric factors are dominant in the expression of methylchrysene diol-epoxide mutagenicity in S. typhimurium and suggest that the molecular shape of the 5-methyl substituted diol-epoxide leads to a unique reaction with DNA associated with high mutagenicity and tumorigenicity.

Chrysenes↗

PubMed1988

Metabolism of K-region derivatives of 1-nitropyrene by rat liver in vitro.

The metabolism of K-region derivatives of 1-nitropyrene was studied in order to provide insight into factors that may contribute to their mutagenic activities and to obtain information on unknown metabolites of 1-nitropyrene. Using 9000 g supernatant from livers of Aroclor-treated rats, 1-nitro-pyrene-4,5-diol, a mutagenic metabolite of 1-nitropyrene, was metabolized to 1-aminopyrene-4,5-diol, a mixture of 1-nitropyrene-4,5,9,10-tetraols, 1-amino-4,5-pyrenedione and 1-nitro-4,5-pyrenedione. 1-Nitro-5H-phenanthro[4,5-bcd]pyran-5-one, a highly mutagenic lactone, was not detected. The metabolism of 1-nitro-4,5-pyrenedione yielded only 1-amino-4,5-pyrenedione; the lactone was not observed. No metabolites were detected when the lactone was incubated under conditions identical to those employed for 1-nitro-4,5-diol and 1-nitro-4,5-pyrenedione. Upon re-examination of the metabolism of 1-nitropyrene, we were able to detect 1-nitropyrene-4,5,9,10-tetraol, 1-amino-4,5-pyrenedione and 1-nitro-4,5-pyrenedione as minor metabolites in addition to the major metabolites reported previously. The results of this study, combined with the mutagenicity data for the K-region derivatives of 1-nitropyrene, suggest that nitroreduction of 1-nitropyrene-4,5-diol and 1-nitro-4,5-pyrenedione to the corresponding hydroxylamines is an important pathway for their metabolic activation in Salmonella typhimurium and their metabolic activation in Salmonella typhimurium and possibly in mammalian systems.

Animals↗

PubMed1988

Tobacco-specific nitrosamines, an important group of carcinogens in tobacco and tobacco smoke.

Tobacco-specific nitrosamines are a group of carcinogens that are present in tobacco and tobacco smoke. They are formed from nicotine and related tobacco alkaloids. Two of the nicotine-derived nitrosamines, NNK and NNN, are strong carcinogens in laboratory animals. They can induce tumors both locally and systemically. The induction of oral cavity tumors by a mixture of NNK and NNN, and the organospecificity of NNK for the lung are particularly noteworthy. The amounts of NNK and NNN in tobacco and tobacco smoke are high enough that their total estimated doses to long-term snuff-dippers or smokers are similar in magnitude to the total doses required to produce cancer in laboratory animals. These exposures thus represent an unacceptable risk to tobacco consumers, and possibly to non-smokers exposed for years to environmental tobacco smoke. The permission of such high levels of carcinogens in consumer products used by millions of people represents a major legislative failure. Indeed, the levels of tobacco-specific nitrosamines in tobacco are thousands of times higher than the amounts of other nitrosamines in consumer products that are regulated by government authorities. Although the role of tobacco-specific nitrosamines as causative factors in tobacco-related human cancers cannot be assessed with certainty because of the complexity of tobacco and tobacco smoke, several lines of evidence strongly indicate that they have a major role, especially in the causation of oral cancer in snuff-dippers. Epidemiologic studies have demonstrated that snuff-dipping causes oral cancer. NNK and NNN are quantitatively the most prevalent known carcinogens in snuff, and they induce oral tumors when applied to the rat oral cavity. A role for NNK in the induction of lung cancer by tobacco smoke is likely because of its organospecificity for the lung. Tobacco-specific nitrosamines may also be involved in the etiology of tobacco-related cancers of the esophagus, nasal cavity, and pancreas. Because they are derived from nicotine, and therefore should be associated only with tobacco, tobacco smoke and other nicotine-containing products, tobacco-specific nitrosamines as well as their metabolites and macromolecular adducts should be ideal markers for assessing human exposure to, and metabolic activation of, tobacco smoke carcinogens. Ongoing research has demonstrated the formation of globin and DNA adducts of NNK and NNN in experimental animals. Sensitive methods for the detection and quantitation of these adducts in humans would provide an approach to assessing individual risk for tobacco-related cancers.(ABSTRACT TRUNCATED AT 400 WORDS)

Humans↗

PubMed1988

DNA and hemoglobin alkylation by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in F344 rats.

Alkylation of DNA and hemoglobin was compared in male F344 rats given a single s.c. injection of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), or its major metabolite formed by carbonyl reduction, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In hepatic DNA, levels of 7-methylguanine and O6-methylguanine formed from NNK 1-48 h after treatment were similar to those formed from NNAL. In nasal mucosa and lung DNA, levels of 7-methylguanine and O6-methylguanine were somewhat higher after treatment with NNK than with NNAL. Acid hydrolysis of hepatic DNA, isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL, gave 180 +/- 48 or 120 +/- 23 mumol/mol guanine, respectively, of 4-hydroxy-1-(3-pyridyl)-1-butanone. Basic hydrolysis of globin isolated from rats treated with either [5-3H]NNK or [5-3H]NNAL gave 4.1 +/- 0.7 or 2.0 +/- 0.1 pmol/mg, respectively of 4-hydroxy-1-(3-pyridyl)-1-butanone. These results indicate that NNAL is not a detoxification product of NNK, since treatment of rats with NNAL results in modifications of DNA which are qualitatively and quantitatively similar to those observed upon treatment with NNK. Alkylation of DNA and globin by NNAL may result mainly from its metabolic reconversion to NNK.

Alkylating Agents↗

PubMed1988

Approaches to the development of assays for interaction of tobacco-specific nitrosamines with haemoglobin and DNA.

The tobacco-specific, nicotine-derived nitrosamines 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are among the most important carcinogens in tobacco and tobacco smoke. Treatment of Fischer 344 rats with these carcinogens resulted in alkylation of haemoglobin and DNA by the 4-(3-pyridyl)-4-oxobutyl group formed during their metabolism. This alkyl group can be detached from globin or DNA under mild hydrolytic conditions as 4-hydroxy-1-(3-pyridyl)-1-butanone, which appears to be a potentially useful dosimeter for human exposure to, and activation of, tobacco-specific nitrosamines.

Animals↗

PubMed1987

Contrasting disposition and metabolism of topically applied benzo(a)pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mouse epidermis in vivo.

Whereas extensive evidence indicates that 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) is a major ultimate carcinogen of benzo(a)pyrene (BaP) in mouse skin, tumorigenicity studies have consistently shown that anti-BPDE is less active then BaP in this model system. In order to investigate factors responsible for this apparent contradiction, we have compared the disposition, metabolism, and DNA binding of [3H]BaP, (+/-)-trans-7,8-[14C]dihydroxy-7,8-dihydrobenzo(a)pyrene [(+/-)-[14C]BaP-7,8-diol), and (+/-)-anti-[3H]BPDE in mouse epidermis in vivo. There were remarkable differences in the total radioactivity recovered in epidermis at various times after topical application of BaP, BaP-7,8-diol, and anti-BPDE. BaP and its metabolites were removed from epidermis gradually (t1/2 approximately equal to 2 h). However, 60-65% of anti-BPDE disappeared from mouse epidermis within 3 min of application, while a second slower phase of removal of radioactivity was observed between 8 min and 2 h. The kinetics of removal of BaP-7,8-diol and its metabolites were intermediate between those of BaP and anti-BPDE. The half-life of anti-BPDE in mouse epidermis was measured by trapping it with 2-mercaptoethanol. The initial half-life was about 6 min, similar to that observed in vitro. However, following the initial rapid penetration of anti-BPDE through epidermis most of the remaining material became immobilized in an epidermal binding site in which its half-life was greater than 2 h. Qualitatively, the metabolite patterns of BaP, BaP-7,8-diol, and anti-BPDE were similar to expectations based on in vitro studies. However, the kinetics of metabolite formation from BaP were different from those of BaP-7,8-diol or anti-BPDE. The extents of formation of anti-BPDE-DNA adducts 24 h after application of BaP, BaP-7,8-diol, or anti-BPDE to mouse skin were similar despite the fact that the levels of anti-BPDE present in epidermis were about 50 to 100 times greater after application of BaP-7,8-diol or anti-BPDE than after application of BaP. The results of this study demonstrate that the quantitative aspects of BaP-7,8-diol and anti-BPDE metabolism and disposition in mouse skin are different from those of BaP and indicate that the relatively low tumorigenicity of BaP-7,8-diol and anti-BPDE in mouse skin may be partially attributable to differences between the disposition of these metabolites when topically applied compared to when they are generated intracellularly from BaP.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗

PubMed1987

Enhancing effect of a bay region methyl group on tumorigenicity in newborn mice and mouse skin of enantiomeric bay region diol epoxides formed stereoselectively from methylchrysenes in mouse epidermis.

The stereochemistry of diol epoxide formation in mouse epidermis upon topical application of [3H]-1R,2R-dihydroxy-1,2-dihydro-5-methylchrysene ([3H]-5-MeC-1R,2R-diol) and [3H]-6-MeC-1R,2R-diol, and the tumorigenicity in mouse skin and in newborn mice of the R,S,S,R and S,R,R,S enantiomers of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (5-MeC-1,2-diol-3,4-epoxide), 5-MeC-7,8-diol-9,10-epoxide, and 6-MeC-1,2-diol-3,4-epoxide were examined. Analysis of tetraols and their derived tetraacetates present in mouse epidermis, 2 h after application of [3H]-5-MeC-1R,2R-diol or [3H]-6-MeC-1R,2R-diol, demonstrated greater than 90% stereoselectivity in formation of 5-MeC-1R,2S-diol-3S,4R-epoxide and 6-MeC-1R,2S-diol-3S,4R-epoxide. Taken together with previous data, these results demonstrate that there is a high degree of stereoselectivity for formation of R,S,S,R enantiomers of 5-MeC- and 6-MeC-1,2-diol-3,4-epoxides in mouse skin. The results of the tumorigenicity studies in mouse skin and in newborn mice clearly demonstrated that 5-MeC-1R,2S-diol-3S,4R-epoxide was the most tumorigenic of the diol epoxide enantiomers tested; 6-MeC-1R,2S-diol-3S,4R-epoxide was inactive. The results of this study show that the high tumorigenicity of 5-MeC compared to 6-MeC is due to the remarkable tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide which, in contrast to 6-MeC-1R,2S-diol-3S,4R-epoxide, has a methyl group in the same bay region as the epoxide ring. We propose that such methyl bay region diol epoxides of other carcinogenic methylated polynuclear aromatic hydrocarbons will also show unique tumorigenic properties.

Animals↗

PubMed1987

High stereoselectivity in mouse skin metabolic activation of methylchrysenes to tumorigenic dihydrodiols.

The stereoselectivity of mouse skin metabolic activation to dihydrodiols of the strong carcinogen 5-methylchrysene (5-MeC) and the weak carcinogen 6-methylchrysene (6-MeC) was investigated. Synthetic 1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol), 5-MeC-7,8-diol, and 6-MeC-1,2-diol were resolved into their R,R- and S,S-enantiomers by chiral stationary phase high performance liquid chromatography. The absolute configurations of the enantiomers were assigned by their circular dichroism spectra. Using these enantiomers as standards, the metabolism of 5-MeC and 6-MeC in vitro in rat and mouse liver and in vivo in mouse epidermis was investigated. Only the R,R-enantiomers of each dihydrodiol predominated (greater than 90%). The dihydrodiol enantiomers were tested for tumor initiating activity on mouse skin. In each case, the R,R-dihydrodiol enantiomer was significantly more tumorigenic than the S,S-enantiomer. The most tumorigenic compound was 5-MeC-1R,2R-diol; it was significantly more active than either 5-MeC-7R,8R-diol or 6-MeC-1R,2R-diol. The results of this study demonstrate that there is a high degree of stereoselectivity in the metabolic activation of 5-MeC and 6-MeC to proximate tumorigenic dihydrodiols in mouse skin. The bay region methyl group has no effect on the stereoselectivity of activation to 1,2-dihydrodiol metabolites in the chrysene system.

Animals↗

PubMed1987

Formation of hemoglobin adducts upon treatment of F344 rats with the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and N'-nitrosonornicotine.

[5-3H]4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone ([5-3H]NNK), [C3H3]NNK, and [5-3H]N'-nitrosonornicotine ([5-3H]NNN) were administered to F344 rats by i.p. injection. Levels of tritium present per milligram globin, 24 h after treatment were 720 fmol (0.1% of dose) for [5-3H]NNK, 640 fmol for [C3H3]NNK, and 370 fmol for [5-3H]NNN. Tritium was detectable in globin 7-8 weeks after treatment with [5-3H]NNK or [5-3H]NNN. Approximately 10-15% of the bound tritium in the globin of rats treated with [5-3H]NNK was released upon incubation of the globin with dilute NaOH or HCl. The released material was identified as 4-hydroxy-1-(3-pyridyl)-1-butanone; it was detectable in globin for 6 weeks (t1/2 = 9.1 days) after administration of [5-3H]NNK. 4-Hydroxy-1-(3-pyridyl)-1-butanone was also formed upon NaOH treatment of globin isolated from rats injected with [5-3H]NNN or [5-3H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone. The formation of 4-hydroxy-1-(3-pyridyl)-1-butanone under these conditions is consistent with a mechanism by which 4-(3-pyridyl)-4-oxobutyldiazohydroxide is produced upon metabolic alpha-hydroxylation of NNK or NNN and binds to globin of hemoglobin, yielding an adduct which is readily hydrolyzed by acid or base. Support for this mechanism was obtained by in vitro experiments. Levels of 4-hydroxy-1-(3-pyridyl)-1-butanone released upon base treatment of globin were 50 times greater after incubation of rat hemoglobin with [5-3H]4-(carbethoxynitrosamino)-1-(3-pyridyl)-1-butanone than with either [5-3H]NNK or [5-3H]4-hydroxy-1-(3-pyridyl)-1-butanone. The results of this study suggest methods that might be applicable for assessing the molecular dosimetry of NNK and NNN in individuals exposed to tobacco and tobacco smoke.

Animals↗

PubMed1987

Development of a monoclonal antibody-based immunoassay for cyclic DNA adducts resulting from exposure to crotonaldehyde.

In order to develop an immunoassay for DNA modifications resulting from exposure to crotonaldehyde, monoclonal antibodies specific for the 8R,6R- and 8S,6S-stereoisomers of 3-(2-deoxy-beta-D-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8-hydroxy-6 - methylpyrimido[1,2-a]purine-10(3H)one were produced. These cyclic 1,N2-propanodeoxyguanosines are formed in DNA exposed to crotonaldehyde in vitro. Three of the four antibodies were most specific for one stereoisomer while the fourth was most specific for the other stereoisomer. Fifty % inhibition of binding in an enzyme-linked immunoabsorbent assay using two of these antibodies and capable of detecting 0.5 mumol of 1,N2-propanodeoxyguanosine per mol of deoxyguanosine was developed. The method was validated by comparison to results obtained with fluorescence assay.

Aldehydes↗

PubMed1987

Formation and tumorigenicity of benzo[b]fluoranthene metabolites in mouse epidermis.

The metabolism in mouse epidermis of benzo[b]fluoranthene (BbF) was studied. [3H]BbF was applied topically, mice were killed at various intervals, and metabolites were extracted from the epidermis and analyzed by h.p.l.c. The major metabolites were identified by comparisons to standards as 4-, 5-, and 6-hydroxyBbF. Sulfate and glucuronide conjugates of these hydroxyBbF were also detected. Minor metabolites included 12-hydroxyBbF, BbF-1,2-diol, and BbF-11,12-diol. BbF-9,10-diol, the only known tumorigenic oxygenated derivative of BbF, was not detected. The further metabolism of BbF-9,10-diol was studied in vitro, using rat liver 9000 g supernatant. The major metabolites were identified by their spectral characteristics as 5- and 6-hydroxyBbF-9,10-diol. Little if any BbF-9,10,11,12-tetraol was detected. 5- and 6-HydroxyBbF-9,10-diol were not detected as metabolites of [3H]BbF in mouse epidermis. Several known and potential BbF metabolites--BbF-1,2-diol, BbF-11,12-diol, BbF-9,10-diol, BbF-9,10-diol-11,12-epoxide, 5- and 6-hydroxyBbF-9,10-diol, 1-hydroxyBbF, 5-hydroxyBbF, and 6-hydroxyBbF--were tested for tumor initiating activity on mouse skin. Among these, only BbF-9,10-diol showed high tumorigenic activity, but no evidence has been obtained for its formation in vivo from BbF. These studies do not support the hypothesis that BbF is metabolically activated through formation of the bay region diol epoxide, BbF-9,10-diol-11,12-epoxide.

Animals↗

PubMed1987

Distribution and metabolism of N'-nitrosonornicotine in the miniature pig.

The distribution and metabolism of [5-3H]N'-nitrosonornicotine ([5-3H]NNN) was studied in three 18-day-old miniature pigs. [5-3H]NNN was administered by intracardiac administration into the right ventricle of the heart to mimic uptake by the lung. Whole body autoradiograms taken 15-220 min after treatment showed high levels of radioactivity in the mandibular and parotid salivary glands, Harder's gland, lacrimal glands, glands of the snout and respiratory part of the nasal cavity, and the melanin of the eyes and skin. Bound radioactivity was most abundant in the nasal mucosa and liver. Analysis of tissues by h.p.l.c. showed the presence of high levels of [5-3H]NNN in the mandibular glands and Harder's gland. Levels of [5-3H]NNN and its metabolites were determined in arterial and venous serum, 0.5-220 min after injection. The disappearance of [5-3H]NNN from serum was biphasic. 4-Oxo-4-(3-pyridyl) butyric acid, a metabolite of [5-3H]NNN resulting from 2'-hydroxylation, which is a suspected activation pathway, was detected 0.5 min after injection and appeared to reach a steady state 2-220 min after injection. 4-Hydroxy-4-(3-pyridyl)butyric acid, from 5'-hydroxylation of [5-3H]NNN, and norcotinine, from denitrosation, were also rapidly formed. These experiments are the first in which the appearance of NNN metabolites in blood has been measured. The ratio of 2'-hydroxylation to 5'-hydroxylation varied from 0.27 to 0.60 in arterial serum and from 0.33 to 0.49 in venous serum in the period from 2-220 min. [5-3H]NNN accumulated in the stomach contents such that its levels were greater than those in arterial or venous serum, 60 min after injection. The results of this study demonstrate that the miniature pig is a useful model for the investigation of nitrosamine metabolism and indicate some similarities and differences in metabolism and distribution compared with the rat.

Animals↗

PubMed1987

Effects of alpha-deuterium substitution on the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its analogues substituted with deuterium at the methylene carbon, 4,4-dideutero-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [4,4-D2)NNK], and the methyl carbon, 4-(trideuteromethylnitrosamino)-1-(3-pyridyl)-1-butanone [(CD3)NNK], adjacent to the N-nitroso group were tested for tumorigenicity in F344 rats. Each compound was administered by 60 s.c. injections over a 20-week period such that the total doses were either 1.0 or 0.33 mmol/kg. The experiment was terminated after 104 weeks. Survival of the rats treated with the higher dose of (4,4-D2)NNK was significantly less than survival in the groups treated with the same doses of NNK or (CD3)NNK. Target tissues were liver, lung and nasal cavity for all three compounds. The higher dose of (4,4-D2)NNK induced higher numbers of nasal tumors and malignant nasal tumors than did NNK. The lower dose of (4,4-D2)NNK induced a higher number of nasal tumors than did NNK. No other significant differences in tumor incidence were observed. The results suggest that 4-(3-pyridyl)-4-oxobutylation of DNA might be important in induction of nasal cavity tumors by NNK.

Animals↗

PubMed1987

Comparative metabolism and DNA binding of 6-nitro-5-methylchrysene and 5-methylchrysene.

The metabolic activation in mouse skin of the strong carcinogen, 5-methylchrysene (5-MeC) was compared to that of the inactive compound, 6-nitro-5-methylchrysene (6-NO2-5-MeC). Metabolites of 6-NO2-5-MeC, formed using rat liver homogenates, were identified based on their spectral properties and were used as markers for studies performed in vivo. In mouse epidermis in vivo, the identified metabolites of 6-NO2-5-MeC were trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene (6-NO2-5-MeC-1,2-diol), the precursor to a bay region dihydrodiol epoxide, trans-9,10-dihydro-9,10-dihydroxy-6-nitro-5-methylchrysene, and 6-nitro-5-hydroxymethylchrysene. The levels of 6-NO2-5-MeC-1,2-diol formed in mouse epidermis from 6-NO2-5-MeC were greater than those of the proximate carcinogen trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene (5-MeC-1,2-diol) formed from 5-MeC. The further metabolism of 6-NO2-5-MeC-1,2-diol was examined in mouse epidermis under conditions similar to those described previously for 5-MeC-1,2-diol. The extents of formation of 1,2,3,4-tetraols from both dihydrodiols were similar. The chromatographic patterns of DNA adducts formed in mouse epidermis from 6-NO2-5-MeC and 5-MeC were qualitatively similar; however, the extent of formation of DNA adducts from 5-MeC was 15-fold greater than from 6-NO2-5-MeC. The reactions between calf thymus DNA and the bay region 1,2-diol-3,4-epoxides of 5-MeC and 6-NO2-5-MeC were compared; the levels of adducts formed from the bay region diol epoxide of 5-MeC were about four times greater than those formed from the bay region diol epoxide of 6-NO2-5-MeC. The results indicate that the relatively low DNA binding in vivo of 6-NO2-5-MeC may be responsible for its apparent lack of tumorigenicity compared to 5-MeC. It is likely that nitro substitution at the 6-position of 5-MeC interferes with the structural requirements of the 1,2-diol-3,4-epoxide which are necessary for specific DNA interactions.

Animals↗

PubMed1987

Investigations on the molecular dosimetry of tobacco-specific N-nitrosamines.

Approaches for assessing molecular dosimetry of 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) in humans by measurement of haemoglobin or DNA adducts are discussed. NNK and NNN form haemoglobin adducts in Fischer 344 rats. Acid or base hydrolysis of the globin gives 4-hydroxy-1-(3-pyridyl)-1-butanone, which can be detected in rat blood up to six weeks after injection of NNK; it may be a useful marker for assessing uptake and metabolic activation of NNK and NNN in tobacco consumers. NNK and its major metabolite, 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAI), methylated DNA of rat liver, lung and nasal mucosa to similar extents. NNAI is formed in human tissues from NNK, but immunoassays for O6-methyldeoxyguanosine (O6-medGuo) in exfoliated oral cells from snuff-dippers have been negative. NNK is also expected to form pyridyloxobutyl adducts in DNA; 32P-postlabelling assays for these adducts are being developed and appear to hold promise for detecting NNK- or NNN-DNA adducts in vivo.

Animals↗

PubMed1987

A study of snuff carcinogenesis.

Dry snuff contains high levels of tobacco-specific N-nitrosamines (TSNA); their concentrations exceed by more than 100 times the quantities of nitrosamines found in any other consumer product. The concentrations of TSNA are similar in dry snuff and in the more popular moist snuff. In addition to the four TSNA identified earlier [N'-nitrosonornicotine (NNN), 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosoanatabine (NAT) and N'-nitrosoanabasine (NAB)], two new nitrosamines were detected in snuff, namely 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAl; 0.07-0.15 ppm) and 4-(N-nitrosomethylamino)-4-(3-pyridyl)-1-butanol (iso-NNAl; 0.06-1.1 ppm). After oral swabbing with a mixture of NNN and NNK, rats developed tumours of the oral cavity and lung, showing that these TSNA are not only organ-specific carcinogens but can also induce local tumours. After swabbing an extract of snuff containing the same concentrations of NNN and NNK, significantly fewer tumours were induced in the oral cavity and lung, indicating inhibition of the tumorigenic activity of the TSNA by other snuff constituents.

Animals↗

PubMed1986

The reemergence of smokeless tobacco.

Smokeless tobacco (snuff and chewing tobacco) is reemerging as a popular form of tobacco, particularly among male adolescents. In different regions of the United States, from 8 to 36 percent of male high-school students are regular users. The use of smokeless tobacco has been shown to cause oral-pharyngeal cancer. The strongest link is with cancers of the cheek and gum. White mucosal lesions (leukoplakia) are found in 18 to 64 percent of users, often at the site where the tobacco was held. Other associations have been suggested for cancers of the esophagus, larynx, and pancreas. Nitrosamines, found in high concentrations in smokeless tobacco, most likely have a role in its carcinogenicity. Other health problems include periodontal disease, acute elevations of blood pressure, and dependence. In early 1986, after action at the state level, Congress enacted a federal law requiring health-warning labels on packages of smokeless tobacco and a ban on electronic advertising. Other regulatory measures under consideration include raising state and federal excise taxes, tightening controls on advertising, and prohibiting sales to minors. In view of the recent growth of this problem, policy makers are taking the opportunity to intervene with preventive measures to protect a new generation of tobacco users.

Adolescent↗

PubMed1986

The effect of chronic ethanol consumption on the tumorigenicity of N-nitrosopyrrolidine in male Syrian golden hamsters.

The effect of oral administration of ethanol on the tumorigenicity of N-nitrosopyrrolidine (NPYR) in chow-fed male Syrian golden hamsters has been investigated. Groups of hamsters were given tap water, 7.4% ethanol or 18.5% ethanol-water mixtures 4 weeks prior to and throughout the carcinogen administration period. A total dose of 1 mmol NPYR was administered by intraperitoneal injection to both tap water and ethanol-consuming animals over a 25-week period. Twenty-four hours after the last injection, ethanol-consuming animals were returned to tap water. In control animals treated with NPYR we observed 3/26 animals with tracheal papillomas, and 6/26 animals with hepatic neoplastic nodules. In animals receiving 7.4% ethanol-water mixtures, we observed 6/26 tracheal papillomas, and 17/26 hepatic neoplastic nodules. Similar results were observed in animals receiving 18.5% ethanol. These data indicate that chronic administration of ethanol to chow-fed hamsters increases the incidence of hepatic neoplastic nodules although no differences in the two levels of ethanol were observed.

Alcoholism↗