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PubMed1992

New potential chemopreventive agents for lung carcinogenesis of tobacco-specific nitrosamine.

Cigarette smoking is the major cause of lung cancer in humans. The continuous increase in the prevalence of cigarette smoking worldwide demands a practical means to circumvent this serious health problem. Our research has focused on the development of new chemopreventive agents against lung carcinogenicity of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Several aromatic isothiocyanates have been identified as effective inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. Phenethyl isothiocyanate, a natural constituent of cruciferous vegetables, protects F344 rats and A/J mice from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis. The alkyl chain length in the aromatic isothiocyanates is an important structural feature for the inhibitory potency. The inhibitory efficacy increases as the alkyl chain elongates up to 6 carbon atoms. Thus, 6-phenylhexyl isothiocyanate is approximately 50 to 100 times more potent than phenethyl isothiocyanate. The remarkable efficiency of 6-phenylhexyl isothiocyanate suggests its potential as a chemopreventive agent in intervention trials. The tissue distribution and excretion of phenethyl isothiocyanate were studied in mice. Two major urinary metabolites were identified as the mercaptopyruvic acid and the N-acetylcysteine conjugates. A urinary marker was developed to quantitate the uptake of phenethyl isothiocyanate in humans after consumption of watercress, a cruciferous vegetable rich in gluconasturtiin, the glucosinolate precursor of phenethyl isothiocyanate. Considering the anticarcinogenic activity of phenethyl isothiocyanate, this marker may eventually be useful in assessing the role of dietary phenethyl isothiocyanate uptake in lung cancer risk.

Adenoma↗
PubMed1992

Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants.

In this study we examined the effects of green tea and its major components, (-)-epigallocatechin gallate (EGCG) and caffeine, on the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice. We also studied the effects of green tea and EGCG on O6-methylguanine and 8-hydroxydeoxyguanosine (8-OH-dGuo) formation in lung tissues caused by NNK treatment. Mice were given 2% tea, 560 ppm EGCG, or 1120 ppm caffeine in drinking water for 13 weeks. During this time, NNK (11.65 mg/kg body weight) was administered by gavage three times weekly for 10 weeks from weeks 3 to 12. The bioassay was terminated 6 weeks after the last NNK treatment. Mice treated with NNK developed 22.5 lung adenomas per mouse, whereas NNK-treated mice that drank green tea or EGCG as drinking water developed only 12.2 (P less than 0.01) and 16.1 (P less than 0.05) tumors per mouse, respectively. Mice that drank green tea or caffeine solution showed lower body weight gains, although little difference in water and diet consumption was noted in these groups. While green tea and EGCG exerted little effect on the formation of O6-methylguanine, a critical DNA lesion in NNK lung tumorigenesis, both treatments suppressed the increase of 8-OH-dGuo levels in mouse lung DNA. The inhibition of 8-OH-dGuo formation in lung DNA by green tea and EGCG is consistent with their ability to inhibit lung tumorigenesis by NNK. Because 8-OH-dGuo is a DNA lesion caused by oxidative damage, these results suggest that the mechanism of inhibition by green tea and EGCG in NNK-induced lung tumorigenesis is due at least partly to their antioxidant properties.

8-Hydroxy-2'-Deoxyguanosine↗
PubMedDate not supplied

Method development for the analysis of N-nitrosodimethylamine and other N-nitrosamines in drinking water at low nanogram/liter concentrations using solid-phase extraction and gas chromatography with chemical ionization tandem mass spectrometry.

N-nitrosodimethylamine (NDMA) is a probable human carcinogen of concern that has been identified as a drinking water contaminant. U.S. Environmental Protection Agency Method 521 has been developed for the analysis of NDMA and 6 additional N-nitrosamines in drinking water at low ng/L concentrations. The method uses solid-phase extraction with coconut charcoal as the sorbent and dichloromethane as the eluent to concentrate 0.50 L water samples to 1 mL. The extracts are analyzed by gas chromatography-chemical ionization tandem mass spectrometry using large-volume injection. Method performance was evaluated in 2 laboratories. Typical analyte recoveries of 87-104% were demonstrated for fortified reagent water samples, and recoveries of 77-106% were demonstrated for fortified drinking water samples. All relative standard deviations on replicate analyses were < 11%.

Charcoal↗
PubMed1991

Synthesis of (+/-)-N-2-methylpropyl-N-1'-methylacetonyl-nitrosamine.

N-2-methylpropyl-N-1-methylacetonyl-nitrosamine (NMAMPA), first isolated from moldy and normal foods, was synthesized by chemical means. The structure and molecular weight of the synthetic NMAMPA were elucidated by spectrometry. A combination of spectral and chromatographic data indicated that the synthetic NMAMPA is identical to that obtained naturally. Synthetic NMAMPA is a racemic modification, and a carcinogen which can induce esophageal and forestomach cancer in rats.

Carcinogens↗
PubMedDate not supplied

Quantitation of the nitrosamine 2-ethylhexyl-4-(N-methyl-N-nitrosoamino) benzoate (NPABAO) in sunscreen products.

We have devised a method to quantitate the nitrosamine, 2-ethylhexyl-4-(N-methyl-N-nitrosoamino) benzoate (NPABAO), in commercial products containing the sunscreen ingredient, Padimate O. The method involves a minimum of cleanup steps to afford a nonaqueous extract from product emulsions suitable for analysis by a liquid chromatograph interfaced to a thermal energy analyzer (LC/TEA). The method is applicable to lotions, creams, and gels. Oils are normally soluble in the mobile phase and can be analyzed directly on the LC/TEA without additional cleanup procedures. The method has a minimum detectable limit of about 30 ppb and yields greater than 80% recovery. It is highly reproducible and generates no NPABAO artifactually prior to quantitation on the LC/TEA. Application of the method to 22 different commercial product formulas disclosed that the level of NPABAO in each of the products is below 250 ppb, with 18 of the products containing less than 100 ppb. Of interest was the observation that musk ketone, a common fragrance constituent, produces a false-positive TEA response that can interfere with accurate analysis of NPABAO content in typical commercial products.

Aniline Compounds↗
PubMed1991

Volatile N-nitrosamines in fish meal, with special reference to the mechanism of formation of N-nitrosothiazolidine.

Volatile N-nitrosamines in 32 commercial Japanese fish meal samples were analysed, and three compounds, N-nitrosodimethylamine, N-nitrosopyrrolidine and N-nitrosothiazolidine (NT), were detected. We also examined the mechanism of formation of NT during fish meal production. Both cysteamine and thiazolidine were found to be precursors of NT. The cysteamine content decreased during boiling and drying of the fish; but that of thiazolidine increased during boiling. N-Nitrosothiazolidine 4-carboxylic acid (NTCA) was formed in sardine meal after treatment with nitrogen dioxide gas, and the rate of formation of NT from NTCA added to sardine meal was as high as 10% when the meal was heated at 160 degrees C for 60 min. We propose two pathways for NT formation during fish meal manufacture: (1) cysteamine----thiazolidine----NT; and (2) cysteine----(thiazolidine 4-carboxylic acid)----NTCA----NT.

Carcinogens↗
PubMed1991

Regional differences in N-nitrosamine content of traditional Chinese foods.

Traditional uncooked and cooked Chinese foods from six provinces with different cancer patterns were analysed for volatile N-nitrosamines (VNA) by gas chromatography-thermal energy analysis. Selected samples were also analysed for N-nitrosamino acids (NAA). N-Nitrosodiethylamine was the VNA found most often (in 91/108 samples; less than 0.2-17.5 micrograms/kg), followed by N-nitrosodimethylamine (in 75/108 samples; less than 0.2-17.3 micrograms/kg). N-Nitrosodipropylamine was detected in 11/108 samples (0.9-6.2 micrograms/g). Samples selected for analysis of NAA on the basis of their VNA content contained one or more NAA, including N-nitrosoproline and N-nitrosothiazolidine 4-carboxylic acid (range, 1.1-115 micrograms/kg; average, 35 micrograms/kg). Both the incidence and pattern of occurrence of VNA suggest that Chinese foods differ from western foods, which would not be expected to contain NAA as frequently nor to contain N-nitrosodipropylamine. The highest percentages of positive samples were from Zhejiang and Fujian provinces (89 and 91%, respectively), and they had the highest average VNA content. Beijing city and Sichuan province gave the lowest percentages of positive samples (75 and 56%, respectively) and the lowest average VNA content.

China↗
PubMed1991

Tobacco-specific nitrosamines in commercial cigarettes: possibilities for reducing exposure.

Tobacco-specific nitrosamines (TSNA) are powerful carcinogens found in tobacco and tobacco smoke in relatively high concentrations. Tar delivery, which is generally accepted as an index for the carcinogenic potential of cigarette smoke, must be declared in most European countries. In this investigation of more than 170 types of commercial cigarettes from several European countries and the USA, no correlation was observed between tar delivery and mainstream smoke concentration of N'-nitrosonornicotine (NNN) and 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK). Therefore, although crucial, tar delivery alone is not a sufficient index for the carcinogenic potential of cigarette smoke. It is proposed that TSNA concentrations be determined for characterization of the carcinogenic potential of cigarettes with low and ultra-low tar yields and that these be declared by an additional and adequate parameter. The mainstream smoke concentrations of NNN and NNK are given by the amounts of preformed compounds in tobacco, which is dependent on the nitrate content of the tobacco and the tobacco type. A further important determinant of the exposure of smokers to TSNA is the total volume drawn through a cigarette while smoking, which is dependent on puff volume and puff frequency and which directly influences TSNA transfer. Smokers inhale higher volumes when smoking low-nicotine cigarettes, so that low NNN:nicotine and NNK:nicotine ratios result in decreased exposure to TSNA. Reduction of exposure to TSNA can be achieved by selecting tobaccos with low levels of preformed TSNA (low nitrate content, small amounts of burley tobaccos and stems) and by manufacturing cigarettes with low NNN:nicotine and NNK:nicotine ratios.

Carcinogens↗
PubMed1991

Antimutagenic and anticarcinogenic effects of betel leaf extract against the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK).

Earlier studies showed that betel leaf inhibits the mutagenic action of standard mutagens like benzo[a]pyrene and dimethylbenz[a]anthracene. Since tobacco-specific nitrosamines are the major carcinogens present in unburnt forms of tobacco, we studied the effect of an extract of betel leaf on the mutagenic and carcinogenic actions of one of the most potent, 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK). Betel-leaf extract and hydroxychavicol suppressed the mutagenicity of NNK in both the Ames and the micronucleus test. In studies in mice, betel-leaf extract reduced the tumorigenic effects of NNK by 25%. Concurrent treatment with the extract also inhibited the decreases in levels of vitamin A in liver and plasma induced by NNK. Betel leaf thus has protective effects against the mutagenic, carcinogenic and adverse metabolic effects of NNK in mice.

Animals↗
PubMed1991

Inhibition of tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) tumorigenesis with aromatic isothiocyanates.

4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent tobacco-specific carcinogenic nitrosamine. At low doses, it induces primarily lung tumours in mice, hamsters and rats, regardless of the route of administration. Its unique organ specificity and potency suggest its possible role in the high incidence of lung cancer in smokers. The goal of this study was to find agents that would potentially prevent NNK tumorigenesis. Previous results led us to test phenethyl isothiocyanate (PEITC) on NNK tumorigenesis in a two-year bioassay in Fischer 344 rats. The NNK-treated group developed 80% lung tumour incidence, whereas NNK-treated rats fed PEITC diets had only 40% lung tumour incidence. Incidences in other organs were not affected by this treatment. We also tested PEITC in a 16-week, short-term bioassay against NNK-induced lung adenomas in A/J mice. Pretreatment of mice with PEITC by gavage at four daily doses of 5 mumol or 25 mumol reduced the formation of NNK-induced lung adenomas by 70% or 100%, respectively. Interestingly, benzyl isothiocyanate and phenyl isothiocyanate, the lower homologues of PEITC, were inactive in this bioassay. Using a protocol similar to that used in the bioassays, PEITC was shown to decrease DNA methylation by NNK in the lungs of rats and mice and suppress the metabolism of NNK by mouse lung microsomes. These results are consistent with the previous data, suggesting that the inhibition of NNK-induced lung tumour formation by PEITC is a consequence of reduced DNA methylation caused by inhibition of NNK metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[The effect of lysine-enriched bread on the formation of N-nitrosamines from their precursors in the stomach of dogs].

Data are presented on nitrosamine (NA) formation in the stomach of dogs after per os intake of their precursors--morpholine (or diethylamine) and sodium nitrite. It has been shown that bread enriched with lysine given to dogs in combination with the precursors promotes a five-six-fold reduction of carcinogenic NA formation in the dog's stomach as compared to the control.

Animals↗
PubMedDate not supplied

Gas chromatographic-chemiluminescence method for determination of volatile N-nitrosamines in minced fish-meat and surimi-meat frankfurters: collaborative study.

A collaborative study was carried out on a solid-phase extraction method for separating volatile N-nitrosamines, particularly N-nitrosodimethylamine (NDMA), from combination minced fish or surimi-meat frankfurters with detection by gas chromatography-chemiluminescence (thermal energy analyzer). The results from the 10 collaborators were evaluated using the most recent AOAC guidelines for determining outliers and for the analysis of variance. For NDMA, repeatability standard deviations, sr, ranged from 0.56 to 2.25; repeatability relative standard deviations, RSDr, ranged from 8.9 to 11.5%. Reproducibility standard deviations, SR, for NDMA ranged from 1.40 to 6.49, and reproducibility relative standard deviations, RSDR, ranged from 24.2 to 28.9%. Our data compared favorably to the reproducibility (RSDR) curve of Horwitz. The method has been adopted official first action by AOAC.

Chromatography, Gas↗
PubMed1990

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is an active transplacental carcinogen in Syrian golden hamsters.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent carcinogen in adult laboratory rodents. Our previous studies have shown that NNK crosses the placenta in pregnant hamsters and is metabolized into DNA-methylating and clastogenic intermediates by fetal respiratory tract tissues. Based on these findings, we have tested the transplacental carcinogenicity of NNK in this species. Groups of pregnant hamsters were given s.c. injections of single or multiple doses of NNK (cumulative dose range, 50-300 mg/kg) on day 15 (last day of gestation) or on days 13, 14, and 15 of gestation. Within 1 year after treatment, up to 70% of the offspring developed tumors in various organs, including respiratory tract, nasal cavity, adrenal glands, pancreas, and liver. No tumors were found in the control hamsters treated with the vehicle (trioctanoin) alone. The overall tumor incidence was proportional to the cumulative dose. Females had a generally higher tumor incidence than males.

Animals↗
PubMed1990

Tobacco-specific nitrosamines in European and USA cigarettes.

More than 170 types of commercial cigarettes from several European countries and the USA were analyzed for tobacco-specific nitrosamines (TSNA) in tobacco and mainstream smoke as well as for nitrate in tobacco. The cigarettes included filter and nonfilter cigarettes with different tar and nicotine yields. The observed range for N'-nitrosonornicotine (NNN) was from 4 to 1353 ng/cigarette in mainstream smoke and from 45 to 12454 ng/cigarette in tobacco. For 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) the values were between not detected (less than 4 ng/cigarette) and 1749 ng/cigarette in mainstream smoke and between not detected (less than 50 ng/cigarette) and 10745 ng/cigarette in tobacco. Nitrate levels ranged from 0.6 to 19.4 mg/cigarette. The TSNA levels for the cigarettes from the different countries investigated were in a similar range with the exception of few individual brands. The results demonstrated that there is no correlation between TSNA and tar deliveries in mainstream smoke. The TSNA deliveries in mainstream smoke depend on the amount or preformed TSNA in the actual tobacco composition, which is influenced by the nitrate level of the tobacco and the tobacco type. According to these results the tar delivery, although crucial, is not a sufficient index for the biological activity and the carcinogenic potential of cigarette smoke. Reduction of TSNA exposure can be achieved by selecting tobaccos with low levels of preformed TSNA in tobacco, which means a low nitrate content and reduction of the amount of Burley tobaccos and stems in blended cigarettes.

Chromatography, Gas↗
PubMed1989

Preventive action of vitamin C on nitrosamine formation.

N-Nitroso compounds are known to form endogenously in the human stomach from the precursors nitrite as well as secondary and tertiary amines. Ascorbic acid has been found to be an effective blocking agent for this process of formation of carcinogenic substances, both in vitro and in vivo. The mechanism by which ascorbic acid reacts is chemical in nature and results in the formation of NO and dehydroascorbic acid. Since NO can be recycled in the presence of O2 to form [NO]x, which is capable of additional nitrosation, greater than stoichrometric amounts of ascorbate are required for effective inhibition in vivo. The efficacy of ascorbic acid for inhibition of nitrosamine formation in humans has been demonstrated both clinically and epidemiologically through the use of "Nitrosoproline Test"--of Ohshima and Bartsch.

Ascorbic Acid↗
PubMed1989

Effects of aromatic isothiocyanates on tumorigenicity, O6-methylguanine formation, and metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mouse lung.

Phenethyl isothiocyanate (PEITC), benzyl isothiocyanate (BITC), and phenyl isothiocyanate (PITC) were tested for their abilities to inhibit lung tumorigenesis and O6-methylguanine formation in lung DNA induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice. Pretreatment with PEITC for 4 consecutive days at daily doses of 5 or 25 mumol inhibited tumor multiplicity induced by a single 10-mumol dose of NNK by approximately 70% or 97%, respectively. The 25-mumol daily dose of PEITC also reduced the percentage of animals that developed tumors by 70%. In contrast, both BITC and PITC failed to significantly reduce tumor multiplicity or the percentages of mice that developed tumors. Using an identical dosing regimen, parallel results were observed in the effects of these isothiocyanates on O6-methylguanine formation in the lung, in which PEITC at either dose resulted in considerable inhibition at 2 or 6 h after NNK administration, while BITC or PITC had little effect. PEITC was further tested for its ability to inhibit lung microsomal metabolism of NNK. A single administration of PEITC (5 or 25 mumol) resulted in 90% inhibition of NNK metabolism. These results in conjunction with recent results obtained using F344 rats firmly establish PEITC as an effective inhibitor of NNK lung tumorigenesis and suggest that the basis of this inhibition is the reduction of DNA adduct formation caused by the inhibition of enzymes responsible for NNK activation.

Adenoma↗
PubMed1989

Effect of intravesical instillation of antitumor drugs in the development of N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder tumors in rats.

We examined the effects of intravesical instillation of adriamycin (ADM) and cis-diammine-dichloroplatinum (CDDP) on the development of bladder tumors induced by 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in 115 rats. Intravesical instillation was performed in two ways; continuous administration (5 times a week for 5 weeks) and intermittent administration (once a week). Group 1 (control group) did not receive intravesical instillation. Group 2 I(ADM), group 3 (CDDP) and group 4 (physiological saline) were continuous type. Group 5 (ADM), group 6 (CDDP) and group 7 (physiological saline) received intermittent administration. Bladder weight was significantly higher in group 4 than in groups 1 or 7, and that in groups 2 and 3 than that in group 5 and 6. In groups 2, 3, 5 and 6 bladder weight was almost normal or higher than in the control group, and in group 3 histologically cancer was not seen in one rat. Physiological saline had promoting activity, and ADM and CDDP had both inhibitory and promoting activities. Also, intravesical instillation itself was suggested to promote tumor development under carcinogenic circumstances. We conclude that intermittent intravesical instillation should be performed to inhibit tumor recurrence and intravesical instillation therapy should not be performed clinically for a long period.

Administration, Intravesical↗
PubMed1978

Some effects of phenol- and thiol-nitrosation reactions on N-nitrosamine formation.

C-Nitrosophenols, produced by the nitrosation of phenols, catalyse N-nitrosamine formation. The rate of N-nitrosation of pyrrolidine, catalysed by p-nitroso-o-cresol, is fastest at about pH 5. The catalytic species is thought to be the quinone monoxime tautomer of the nitrosophenol. A possible mechanism for the catalysis is proposed. A reaction of pyrrolidine with nitrite at pH 5.0 is described, which gives enhanced N-nitrosation in the presence of p-cresol. The yield of N-nitrosopyrrolidine (NPYR) is further enhanced when this reaction is carried out under anaerobic conditions. Nitrosocysteine hydrochloride reacts with N-methylaniline at pH 2.65, 5.5 and 9.75 in the absence of nitrite to give N-nitroso N-methylaniline. The N-nitrosation of morpholine and pyrrolidine at pH 9.75 is also effected by nitrosocysteine hydrochloride. The rate of N-nitrosation at this pH decreases with increasing amine basicity. The reaction of nitrosocysteine with N-methylaniline at pH 9.75 under anaerobic conditions leads to a significant reduction in the yield of N-nitroso-N-methylaniline.

Aniline Compounds↗