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S S Hecht

Publications and source records attributed to S S Hecht.

At least 289 records · Page 16Linked to original sources
PubMed1982

N-nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine in hair-care products.

N-Nitroso-N-methyldodecylamine and N-nitroso-N-methyltetradecylamine, which cause urinary bladder tumours in experimental animals, were detected in several hair-care products formulated with N,N-dimethyldodecylamine oxide. Quantitative determinations were made using a gas-liquid chromatograph interfaced with a thermal energy analyser and using [1-14C]N-nitroso-N-methyldodecylamine as an internal standard. The presence of the two nitrosamines was confirmed by high-pressure liquid chromatography with a thermal energy analyser as detector, by photolysis of samples and by combined gas chromatography-mass spectometry. To test the reproducibility of the method, a single shampoo was selected for replicate analysis and was found to contain 90 +/- 8 ppb N-nitroso-N-methyldodecylamine and 37 +/- 11 ppb N-nitroso-N-methyltetradecylamine. Levels of N-nitroso-N-methyldodecylamine in other hair-care products ranged from 11 to 873 ppb and those of n-nitroso-N-methyltetradecylamine from 8 to 254 ppb.

Carcinogens↗
PubMed1982

Tumour initiating activity of dihydrodiols of benzo[b]fluoranthene, benzo[j]fluoranthene, and benzo[k]fluoranthene.

The tumor initiating activities on mouse skin of benzo[b]fluoranthene, (B[b]F), benzo[j]fluoranthene (B[j]F), benzo[k]fluoranthene (B[k]F] and three of their dihydrodiols, 9,10-dihydro-9,10-dihydroxybenzo[b]fluoranthene (B[b]F-9,10-diol), 9,10-dihydro-9,10-dihydroxybenzo[j]fluoranthene (B[j]F-9,10-diol), and 8,9-dihydro-8,9-dihydroxybenzo[k]fluoranthene (B[k]F-8,9-diol) were evaluated. Among the parent hydrocarbons, B[b]F was the most potent tumor initiator, with activity greater than that of B[j]F but less than that of benzo[a]pyrene. B[k]F also showed tumor initiating activity, in contrast to its lack of complete carcinogenic activity on mouse skin. B[b]F-9,10-diol, which can form a bay region dihydrodiol epoxide, was as active as B[b]F. B[j]F-9,10-diol, which would form its dihydrodiol epoxide in a four sided pseudo-bay region, was less active than B[j]F. B[k]F-8,9-diol was inactive. These results, together with parallel metabolic studies, suggest that the formation of bay region dihydrodiol epoxides may not be the major activation mechanism in benzofluoranthene tumorigenesis.

Animals↗
PubMed1982

Identification of metabolites of 5,11-dimethylchrysene and 5,12-dimethylchrysene and the influence of a peri-methyl group on their formation.

We investigated the in vitro metabolism by mouse and rat liver 9000 x g supernatant of the strong tumor initiator, 5,11-dimethylchrysene (5,11-diMeC) and its inactive analogue, 5,12-dimethylchrysene (5,12-diMeC). Ethyl acetate soluble metabolites were separated by h.p.l.c. and identified by their u.v. and m.s. and by comparison to selected synthetic reference standards. Both compounds were converted to dihydrodiols, chrysenols, hydroxymethylchrysenes, and hydroxymethylchrysenols. The peri 12-methyl group of 5,12-diMeC strongly inhibited metabolism at the adjacent 1,2-positions. Thus, the ratio of 7-hydroxy-5,12-diMeC to 1-hydroxy-5,12-diMeC was approximately 100 to 1 when 5,12-diMeC was metabolized by liver supernatants from 3-methylcholanthrene pretreated mice and rats. In addition, 7,8-dihydro-7,8-dihydroxy-5,12-diMeC was preferentially formed over 1,2-dihydro-1,2-dihydroxy-5,12-diMeC by liver supernatants from control, 3-methylcholanthrene pretreated, and Aroclor pretreated animals. In contrast, the presence of a methyl group at the 11 position of 5,11-diMeC did not inhibit formation of 1-hydroxy-5,11-diMeC or 1,2-dihydro-1,2-dihydroxy-5,11-diMeC. Since 1,2-dihydro-1,2-dihydroxy metabolites of 5-methylchrysene derivatives are potential proximate tumorigens, these results may provide a basis for the higher tumorigenicity of 5,11-diMeC than of 5,12-diMeC.

Animals↗
PubMed1982

Regiospecificity in the metabolism of the homologous cyclic nitrosamines, N'-nitrosonornicotine and N'-nitrosoanabasine.

We compared the metabolism in the F-344 rat of the moderately potent esophageal carcinogen N'-nitrosonornicotine (NNN, 2'-(3-pyridyl)-N-nitrosopyrrolidine) and its weakly active homologue N'-nitrosoanabasine (NAB, 2'-(3-pyridyl)-N-nitrosopiperidine). Urine was the major pathway of excretion for both nitrosamines. The major urinary metabolites of dl-NNN resulted from 2'-hydroxylation (8.1% of the dose), 5'-hydroxylation (37.6%), and pyridine N-oxidation (10.8%). The percentages of the dose of the corresponding metabolites of dl-NAB were: 2'-hydroxylation (not detected), 6'-hydroxylation (9.8%), pyridine-N-oxidation (30.0%). Similar results were obtained when the urinary metabolites of l-NNN and l-NAB were compared. In 48 h cultures of rat esophagus, the major metabolites of [2'-14C]dl-NNN resulted from 2'-hydroxylation (47%) and to a lesser extent from 5'-hydroxylation (15%). In contrast the major metabolite of [2'-14C]dl-NAB resulted from 6'-hydroxylation (35%) with lesser amounts from 2'-hydroxylation (8%). 6'-Hydroxylation of [2'-14C]dl-NAB also exceeded 2'-hydroxylation in cultures of 3, 6, 12 or 24 h duration. Pyridine-N-oxidation was not observed in the esophagus for either nitrosamine. These results demonstrate a high degree of regiospecificity in the metabolism of these structurally related nitrosamines. Among the identified urinary metabolites the ratio of alpha-hydroxylation to N-oxidation was 4.2 for NNN and 0.3 for NAB. Among the 48 h esophageal metabolites the ratio of 2'-hydroxylation to 5'- or 6'-hydroxylation was 3.1 for NNN and 0.2 for NAB. The results also suggest a basis for the weak carcinogenicity of NAB: facile excretion as its pyridine-N-oxide and detoxification in the esophagus by 6'-hydroxylation.

Animals↗
PubMed1982

Identification of metabolites of benzo[b]fluoranthene.

The metabolism by rat liver 9000 x g supernatant of the environmental carcinogen benzo[b]fluoranthene was investigated. The major metabolites were identified, by comparison to synthetic samples, as 5- and 6-hydroxybenzo[b]fluoranthene and 4- and 7-hydroxybenzo[b]fluoranthene. The principal dihydrodiol metabolite formed under these conditions was trans-11,12-dihydro-11,12-dihydroxybenzo[b]fluoranthene, which was identified by comparison to the synthetic compound. 1,2-Dihydro-1,2-dihydroxybenzo[b]fluoranthene was identified, by its mass spectrum and by comparison if its u.v. spectrum to that of a synthetic model compound, 11-ethylidene-11H-benzo[b]fluorene. No evidence was obtained for the formation of 7b,8-dihydro-7,8-dihydroxybenzo[b]fluoranthene or trans-9,10-dihydro-9,10-dihydroxybenzo[b]fluoranthene. The latter would be the precursor to a bay region dihydrodiol epoxide of benzo[b]fluoranthene.

Animals↗
PubMed1982

Metabolism of N'-nitrosonornicotine by cultured rat esophagus.

The metabolism of N'-nitrosonornicotine (NNN), an esophageal carcinogen, by organ cultured F-344 rat esophagus was investigated. The major metabolites were separated by h.p.l.c. and were identified by comparison to standards as 4-hydroxy-1-(3-pyridyl)-1-butanone, 4-hydroxy-4-(3-pyridyl)-1-butanol and 4-oxo-4-(3-pyridyl)butyric acid from 2'-hydroxylation of NNN and 4-hydroxy-4-(3-pyridyl)-butyric acid from 5'-hydroxylation of NNN. These results demonstrate that alpha-hydroxylation, which leads to electrophilic diazohydroxides, is the major pathway of metabolism of NNN in cultured F-344 rat esophagus. The extents of formation of the metabolites increased with time and the ratio of products resulting from 2'-hydroxylation to those resulting from 5'-hydroxylation was 4.3 after 1 h, 3.9 after 6 h, 3.4 after 24 h and 3.1 after 48 h. F-344 rat liver slices from the same animals produced metabolites of NNN with a 2'/5'-hydroxylation ratio of 1.4. The 2'/5'-hydroxylation ratio in cultured Syrian golden hamster esophagus was 0.3. These results, together with those of parallel studies of NNN metabolism in A/J mouse lung and Syrian golden hamster trachea indicate that among these tissues, F-344 rat esophagus has a unique ability to preferentially hydroxylate the 2'-position of NNN. The results suggest that 2'-hydroxylation is the key step in the metabolic activation of NNN in rat esophagus.

Animals↗
PubMed1982

Identification of the mutagenic metabolites of fluoranthene, 2-methylfluoranthene, and 3-methylfluoranthene.

The metabolites of fluoranthene, 2-methylfluoranthene, and 3-methylfluoranthene obtained upon incubation with liver homogenate from Aroclor pretreated rats were assayed for mutagenicity in Salmonella typhimurium TA100. The mutagenic metabolites of fluoranthene and 2-methylfluoranthene were identified as 2,3-dihydro-2,3-dihydroxyfluoranthene and 4,5-dihydro-4,5-dihydroxy-2-methylfluoranthene, respectively. In contrast to these results, the major proximate mutagen detected among the in vitro metabolites of 3-methylfluoranthene was 3-hydroxymethylfluoranthene. Comparison of the mutagenic potential of 2-hydroxymethylfluoranthene demonstrated that the latter was a more powerful mutagen. Quantitative analyses of the metabolites of fluoranthene with that of 3-hydroxymethylfluoranthene demonstrated that the latter was a more powerful mutagen. Quantitative analyses of the metabolites of fluoranthene, 2-methylfluoranthene, and 3-methylfluoranthene indicated that similar amounts of dihydrodiols were formed. 4,5-Dihydro-4,5-dihydoxy-3-methylfluoranthene, however, was not found to be a potent mutagenic metabolite. These data suggest that the activation pathway to ultimate mutagens may differ for 2- and 3-methylfluoranthene.

Animals↗
PubMed1982

N-nitrosamines: environmental occurrence, in vivo formation and metabolism.

A number of amines and quaternary ammonium salts can be nitrosated to N-nitrosamines under environmental conditions as well as in vivo. Of the N-nitrosamines which have been bioassayed to date, more than 250 are proven animal carcinogens. In the absence of data which document that N-nitrosamines can be carcinogenic to man, we concur with the International Agency for Research on Cancer that those nitrosamines that were proven carcinogens in at least 2 animal species "should be regarded for practical purposes as if they were carcinogenic to humans" (1). Such evaluation pertains also to N-nitrosodiethanolamine (NDELA), N-nitrosomorpholine (NMOR) and the tobacco-specific N-nitrosamines (TSNA). This presentation discusses the environmental occurrence, analysis, reduction, bioassay data for carcinogenicity and metabolism of these 3 types of nitrosamines. The data at hand make it prudent to encourage reduction of the occurrence of N-nitrosamines in the workplace, in the environment and in food, tobacco and other personal use products. Emphasis should also be placed on research efforts to inhibit the in vivo formation of N-nitrosamines and their metabolic activation to reactive carcinogenic species. The latter efforts require increased knowledge as to the activation of nitrosamines and their reaction with cellular macromolecules including DNA.

Animals↗
PubMed1982

Tobacco specific N-nitrosamines: occurrence and bioassays.

A new GC-TEA method for the analysis of tobacco-specific N-nitrosamines (TSNA) has been developed. Four TSNA have thus far been identified; these are N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosoanatabine (NAT) and N'-nitrosoanabasine (NAB). The method is currently being applied to the development of cigarette filter-tips which will selectively remove these carcinogens from cigarette smoke. Since recent epidemiological studies have established a correlation between snuff dipping and oral cancer, we have analysed leading snuff brands for TSNA. Snuff products from Sweden, Denmark, Bavaria and the USA contained 5-106 mg/kg of the TSNA and the saliva of snuff dippers had TSNA levels of 20-890 micrograms/kg. NNN, NNK and NAB induce benign and malignant tumours of the respiratory tract of mice and rats. We have shown that NNN and NNK induce tumours in the upper respiratory tract of hamsters and that NNK is the most active carcinogen of the TSNA, also inducing adenoma and adenocarcinoma in the hamster lung. The reported chemical analyses and bioassay results support the epidemiological findings on the causal association of tobacco use and cancer in man.

Adult↗
PubMed1982

Influence of bay-region methyl group on formation of 5-methylchrysene dihydrodiol epoxide:DNA adducts in mouse skin.

The binding of tritium-labeled 5-methylchrysene to DNA of CD-1 mouse skin 24 hr after treatment has been studied. DNA was isolated from the treated skin areas of mice and hydrolyzed enzymatically to deoxyribonucleosides, and the hydrolysate was chromatographed on a Sephadex LH-20 column using a methanol:water gradient. The major adducts eluted between 70 and 100 ml (Peak 1), 470 and 590 ml (Peaks 2A to C), and 750 and 850 ml (peak 3). For identification of these products, markers were prepared from 5-methylchrysene bay-region dihydrodiol epoxides. [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene and [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene were synthesized by reacting the corresponding metabolically formed [5-14C]1,2-dihydro-1,2-dihydroxy-5-methylchrysene and [5-14C]7,8-dihydro-7,8-dihydroxy-5-methylchrysene with m-chloroperoxybenzoic acid. The structures of the dihydrodiol epoxides were established by their mass spectra and by hydrolysis to tetrols. Peak 2B was chromatographically indistinguishable, both on Sephadex LH-20 and reverse-phase high-pressure liquid chromatography, from the adduct formed when [5-14C]1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene was reacted with salmon sperm DNA in solution. Similarly, Peak 2A was chromatographically inseparable from the [5-14C]7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene:DNA adduct. Adduct 2B was formed to a greater extent than adduct 2A by the ratio of 2.7 to 1. These data indicate that 5-methylchrysene preferentially forms DNA adducts from the bay-region dihydrodiol epoxide adjacent to the methyl group.

Animals↗
PubMed1982

Identification of mutagenic metabolites formed by C-hydroxylation and nitroreduction of 5-nitroacenaphthene in rat liver.

The metabolism of the mutagen and carcinogen, 5-nitroacenaphthene, by the 9000 x g supernatant from the livers of Aroclor-pretreated rats was studied. The major primary metabolites were 1-hydroxy-5-nitroacenaphthene and 2-hydroxy-5-nitroacenaphthene. These metabolites were oxidized to 1-oxo-5-nitroacenaphthene and 2-oxo-5-nitroacenaphthene, hydroxylated to cis-1,2-dihydroxy-5-nitroacenaphthene and trans-1,2-dihydroxy-5-nitroacenaphthene, and reduced to 1-hydroxy-5-aminoacenaphthene and 2-hydroxy-5-aminoacenaphthene. Reduction of 1- and 2-oxo-5-nitroacenaphthene to 1-oxo- and 2-oxo-5-aminoacenaphthene was also observed. When incubations were carried out in a N2-enriched atmosphere (10% O2 in N2), the major metabolites were 1-hydroxy- and 2-hydroxy-5-nitroacenaphthene and 2-oxo-5-aminoacenaphthene. Selected metabolites were tested for mutagenicity toward Salmonella typhimurium TA 98. The most mutagenic of the metabolites tested, in the presence or absence of rat liver 9000 x g supernatant, were 1-hydroxy-5-nitroacenaphthene and 1-oxo-5-nitroacenaphthene. These results indicate that the 9000 x g supernatant from the livers of Aroclor-pretreated rats is capable of catalyzing both the oxidation and reduction of 5-nitroacenaphthene and that the reduced derivatives of 1-hydroxy- or 2-hydroxy- or 1-oxo- or 2-oxo-5-nitroacenaphthene are proximate mutagens.

Acenaphthenes↗
PubMed1982

N-nitrosodiethanolamine: analysis, formation in tobacco products and carcinogenicity in Syrian golden hamsters.

An analytical GC-TEA method has been developed for the quantitative determination of N-nitrosodiethanolamine (NDELA) in tobacco and tobacco smoke. US smoking and chewing tobaccos and experimental cigarette tobaccos contained between 80 and 420 micrograms/kg of NDELA. Two snuff samples contained 3200 and 6800 micrograms/kg of NDELA. NDELA in mainstream smoke of US cigarettes amounted to 10 - 68 ng per cigarette. Evidence was presented which incriminates diethanolamine as a major precursor for NDELA in tobacco and tobacco smoke. Diethanolamine is used as a solubilizing agent for maleic hydrazide, the major sucker-growth inhibitor for US tobacco crops. NDELA was bioassayed in Syrian golden hamsters by skin painting, swabbing of the oral cavity and by subcutaneous injection. Independently of the form of application, NDELA at the higher dose (500 mg/kg) induced carcinomas of the nasal cavity, papillomas of the trachea and tumours of the larynx in some animals. NDELA uptake through the oral cavity in hamsters is presumably greater than through the skin, judging by the higher tumour yield induced by painting of the oral cavity, compared to skin painting. Studies with 14C-labeled NDELA are currently underway to document this observation quantitiatively. The present analytical data for NDELA in tobacco and tobacco smoke, together with the carcinogenicity data reported here and elsewhere, strongly suggest a review of the use of maleic hydrazide-diethanolamine as sucker-growth inhibitor in the cultivation of tobacco and other crops.

Animals↗
PubMed1981

The influence of methyl substitution of the mutagenicity of nitronaphthalenes and nitrobiphenyls.

A series of nitrobiphenyls, nitronaphthalenes, and their methyl-substituted derivatives were assayed for mutagenicity toward S. typhimurium TA98 and TA100. In assays conducted in the absence of rat liver S9 fraction, substitution of a methyl group ortho to the nitro group decreased mutagenicity (3-methyl-4-nitrobiphenyl, 2-methyl-1-nitronaphthalene, and 3-methyl-2-nitronaphthalene). The mutagenicity of 4-nitrobiphenyl was also inhibited by methyl substitution at the 2'-position (2'-methyl-4-nitrobiphenyl), and at both the 3- and 2'-positions (3,2'-dimethyl-4-nitrobiphenyl). In assays conducted in the presence of rat liver S9 fraction, inhibition of mutagenicity by methyl substitution was demonstrated for 2-methyl-1-nitronaphthalene, 3-methyl-2-nitronaphthalene and 3,2'-dimethyl-4-nitrobiphenyl. Thus, methyl substitution of nitrobiphenyls and nitronaphthalenes generally decreased mutagenicity, when assays were conducted in the absence of rat liver S9 fraction. However, in the presence of rat liver S9 fraction, the inhibitory effect of methyl substitution on mutagenicity was less pronounced. These results contrast to the usual enhancing effect of ortho-methyl substitution of the corresponding aromatic amines and their N-oxidized derivatives (hydroxylamines and C-nitroso compounds).

Animals↗
PubMed1981

Effects of ortho-methyl substituents on the mutagenicity of aminobiphenyls and aminonaphthalenes.

A series of aminobiphenyls and aminonaphthalenes were assayed for mutagenicity toward S. typhimurium, in the presence of rat liver 9000 g supernatant, to investigate the effects of positional isomerism and ortho-methyl substitution. Among the 3 possible aminobiphenyl isomers, only 4-aminobiphenyl was a potent mutagen, showing activity in S. typhimurium TA1538 and TA100, but not TA1535. 4-Amino-3-methylbiphenyl was a more potent mutagen in S. typhimurium TA1538 than was 4-aminobiphenyl, whereas both 3-amino-4-methylbiphenyl and 3-aminobiphenyl were inactive in this strain. 3-Amino-4-methylbiphenyl was mutagenic in S. typhimurium TA100, in contrast to 3-aminobiphenyl. These results demonstrate the enhancing effect of an ortho-methyl group on mutagenicity in the aminobiphenyls, which contrasts to the inhibitory effect of methyl substitution frequently observed in the 4-nitrobiphenyl system. Among the 2-aminonaphthalenes, 2-amino-3-methylnaphthalene was the most mutagenic compound in S. typhimurium TA1538, followed by 2-amino-1-methylnaphthalene and 2-aminonaphthalene. In S. typhimurium TA1535, however, 2-aminonaphthalene was a more potent mutagen than either of the ortho-methyl substituted derivatives. No significant mutagenic activity was observed for either 1-aminonaphthalene or 1-amino-2-methylnaphthalene in S. typhimurium TA1538 and TA1535. However, 1-aminoanaphthalene was weakly mutagenic in S. typhimurium TA 100.

1-Naphthylamine↗
PubMed1981

Effects of fluorine substitution on the tumor initiating activity and metabolism of 5-hydroxymethylchrysene, a tumorigenic metabolite of 5-methylchrysene.

The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 microgram, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90% of the animals, with 9.5 tumors/mouse, 5-MeC gave a 75% incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10 microgram initiating dose were; 5-HOMeC, 45% skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55% skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxy-methylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 microgram. 7-F-5-HOMeC gave 95% tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5% tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 x g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.

Animals↗
PubMed1981

The formation of azoxy-2-phenylethane during the biological oxidation of phenylethylamine by rabbit liver microsomes.

Incubation of phenylethylamine with rabbit liver microsomes, divalent manganese and a NADPH generating system leads to the formation of azoxy-2-phenylethane, among other metabolic products. Approximately 38 nmol of the azoxy compound is formed form 10 mumol of phenylethylamine during a 30 min incubation. Azoxy-2-phenylethane was identified by comparison of its chromatographic (thin-layer, high pressure liquid and gas chromatography) properties with those of an authentic standard and was confirmed by mass spectrometry. The metabolism of phenylethylamine to azoxy-2-phenylethane appears completely dependent on the presence of divalent manganese; no reaction was observed in the absence of this metal or in the presence of equivalent concentrations of cupric ions. Azoxy-2-phenylethane was mutagenic, with S-9 activation, in S. typhimurium strains TA 100 and TA 1535 but not in TA 98 or TA 1537. This report constitutes the first demonstration of the formation of an aliphatic azoxy compound from the corresponding amine by a mammalian system.

Animals↗
PubMed1981

Comprehensive analysis of urinary metabolites of N'-nitrosonornicotine.

A detailed study of the urinary metabolites of N'-nitrosonornicotine has been performed, employing a simple high pressure liquid chromatographic method. The percentage excretion of the principal urinary metabolites was determined over a dose range of 3-300 mg/kg in the F-344 rat, as follows: 4-hydroxy-4-(3-pyridyl)butyric acid (37.1-53.3%, respectively, of the dose), N'-nitrosonornicotine-I-N-oxide (6.7-10.7%), norcotinine (3.2-5.1%), 4-oxo-4-(3-pyridyl)butyric acid (31.1-12.8%), N'-nitrosonornicotine (3.3-5.2%). In the strain A mouse and Syrian golden hamster, the urinary metabolites were qualitatively similar to those observed in the F-344 rat. The interrelationships of the various metabolites of N'-nitrosonornicotine which have been observed in vitro and in vivo were established. The in vitro metabolites resulting from 2'-hydroxylation by liver microsomes, myosmine and 4-hydroxy-I-(3-pyridyl)-1-butanone were converted, by the F-344 rat, primarily to 4-oxo-4-(3-pyridyl)butyric acid as a urinary metabolite. The in vitro metabolite resulting from 5'-hydroxylation by liver microsomes, 2-hydroxy-5-(3-pyridyl)tetrahydrofuran, gave 4-hydroxy-4-(3-pyridyl)butyric acid as its major urinary metabolite, apparently via 5-(3-pyridyl)-tetrahydrofuran-2-one. N'-nitrosonornicotine-I-N-oxide, the remaining major in vitro metabolite, was excreted to a large extent unchanged in F-344 rat urine. The urinary metabolites from 2'-hydroxylation and 5'-hydroxylation of N'-nitrosonornicotine, 4-oxo-4-(3-pyridyl)butyric acid and 4-hydroxy-4-(3-pyridyl)butyric acid, respectively, were not formed from the in vivo metabolite norcotinine and were ot interconverted significantly by the F-344 rat. Thus, these metabolites appear to be reliable indicators for the two possible in vivo alpha-hydroxylations of N'-nitrosonornicotine.

Animals↗