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PubMed1994

Biomarkers for human uptake and metabolic activation of tobacco-specific nitrosamines.

Tobacco-specific nitrosamines are a group of carcinogens formed from nicotine and related tobacco alkaloids. Two of these compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine, are believed to be involved as causative agents for cancers of the lung, oral cavity, esophagus, and pancreas associated with the use of tobacco products. The goal of the studies described here is to develop biomarkers which will allow us to understand the uptake, metabolic activation, and detoxification of these carcinogens in humans. Two metabolites of NNK, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronide, have been identified and quantified in human urine. These metabolites allow assessment of NNK uptake in smokers, tobacco chewers, and people exposed to environmental tobacco smoke. NNK and N'-nitrosonornicotine form hemoglobin and DNA adducts upon metabolic activation by alpha-hydroxylation. These adducts release 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) upon hydrolysis. The released 4-hydroxy-1-(3-pyridyl)-1-butanone can be quantified by gas chromatography-mass spectrometry. A subset of smokers and most tobacco chewers have hemoglobin adduct levels which are higher than detected in nonsmokers. 4-Hydroxy-1-(3-pyridyl)-1-butanone-releasing DNA adducts are higher in lung tissue from smokers than from nonsmokers. These data indicate that some smokers and tobacco chewers are capable of metabolically activating NNK or N'-nitrosonornicotine to intermediates which bind to cellular macromolecules and are, therefore, at potentially higher risk for cancer development. The application of these biomarkers to studies on cancer induction by tobacco products is discussed.

Animals↗
PubMed1978

Effect of protease inhibitors in mice treated with the hepatocarcinogen, hexachlorocyclohexane (alpha-isomer) and the bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine.

Studies were made on the effect of protease inhibitors (pepstatin, leupeptin, and antipain) on the induction of tumors in mice by the alpha-isomer of 1,2,3,4,5,6-hexachlorocyclohexane (alpha-BHC) and by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Animals were given 0.05% alpha-BHC in the diet or 0.05% BBN in their drinking water and then fed on a powder diet supplemented with 0.1% protease inhibitors. The incidence of liver nodular hyperplasias was significantly higher in the group treated with alpha-BHC and leupeptin than in the group treated with alpha-BIC alone, but pepstatin and antipain did not affect induction of liver nodular hyperplasias by alpha-BHC. None of the three protease inhibitors influenced the induction of bladder tumors by BBN.

Animals↗
PubMed1994

Effect of Vicia faba and bran feeding on nitrosamine carcinogenesis and formation.

The goal of this work was to study the effect of the most common Egyptian food items, Vicia faba beans (VF) and bran, on the carcinogenicity of dibutylnitrosamine (DBN) precursors (dibutylamine and nitrite). Mice receiving DBN precursors showed a delayed gain in body weight as well as decreased protein level and 5-nucleotidase activity. Acid ribonuclease, alkaline phosphatase, and DNA level and rate of synthesis were significantly increased compared with corresponding controls. Hepatomas and bladder papillomas developed in 60% and 40% of mice, respectively, after nine months of treatment. On the other hand, administration of VF or bran, in addition to DBN precursors, lessened the damage caused by DBN precursors alone, except DNA level and rate of synthesis were elevated. Alkaline phosphatase was also elevated when bran was administered with DBN precursors. However, these elevations were still less than corresponding elevations in mice receiving DBN precursors alone. The incidence of hepatoma was also reduced to only 20% for both groups. Meanwhile, incidence of bladder papillomas was only 20% in mice receiving VF in addition to DBN precursors, and bladder papillomas were completely absent in mice receiving bran in addition to DBN precursors. In vitro studies were also performed to clarify the effect of VF or bran on diphenylnitrosamine (DPhNA) and its formation from its precursors (diphenylamine and nitrite). The study revealed that VF and bran have the ability to eliminate nitrite and DPhNA from the reaction media and to reduce the rate of formation of DPhNA from its precursors. This reaction depends on the concentration and form of VF or bran and the duration of the reaction. Thus it is concluded that some naturally occurring food items, such as VF and bran, could protect humans against the hazardous effect of nitrosamines and their precursors.

Animals↗
PubMed1993

[Nitrosamine formation via non-prescription drugs?].

Both carcinogenic and non-carcinogenic nitrosamines can be formed under physiological conditions in the human body as a reaction between nitrite and a secondary or tertiary amine. A major part of the population is exposed daily through drinking water to high levels of nitrate, which can be reduced to nitrite. Moreover, nitrate and nitrite are both present in vegetables and nitrite is used in food preservation. Dietary exposure to amines is normally well below 100 mg per day, whereas paracetamol and antazoline, both secondary amines, are used therapeutically at much higher doses. Knowledge about the possible interactions between these widely used drugs and the background exposure to nitrite is presently not available. Therefore, an evaluation of the carcinogenic hazard related to this combination is needed.

Acetaminophen↗
PubMed1977

Effects of sex hormones on oncogenesis in rat urinary bladder by N-butyl-N-(4-hydroxybutyl)-nitrosamine.

The effects of testosterone propionate, estradiol, and estriol on the oncogenesis of male rats' bladder induced by oral administration of the carcinogen N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were examined. There were significant differences between the testosterone propionate-administered and estradiol-administered groups and also between the testosterone propionate-administered and estriol-administered groups in the incidence of bladder tumors.

Animals↗
PubMed1993

Transplacental induction of pancreas tumors in hamsters by ethanol and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

Epidemiological studies suggest that smoking during pregnancy and passive exposure of children to cigarette smoke may increase the cancer risk in children and young adults. We have previously shown that the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is an active transplacental carcinogen in Syrian golden hamsters when administered by s.c. injections to pregnant females. The majority of tumors in the offspring developed in the respiratory tract. Since in smoking women the respiratory tract is the portal of entry of tobacco-related carcinogens, including NNK, we have investigated the transplacental effects of NNK given by intratracheal instillation to pregnant hamsters. The modulating effect of ethanol on the transplacental carcinogenicity of NNK in this system was also investigated because smoking and consumption of alcoholic beverages are observed in pregnant women. Our data show that exposure to NNK via the maternal respiratory tract causes a similar tumor incidence in the offspring as the s.c. route of administration. Ethanol greatly enhanced the carcinogenic response to NNK, and up to 60% of the offspring exposed in utero to ethanol and NNK developed tumors of the exocrine pancreas.

Animals↗
PubMed1996

Assessment of major carcinogenic tobacco-specific N-nitrosamines in Thai cigarettes.

This report presents new findings on the content of cancer-causing tobacco-specific N-nitrosamines (TSNA) in mainstream smoke of nine brands of commercially produced Thai cigarettes, representing about 85% of market share in Thailand. Also tested were two major and popular brands of U.S. cigarettes sold in Thailand, representing about 10% of market share. The cigarettes included filter and nonfilter cigarettes with high, moderate, and low tar and nicotine yields. The observed range for N-nitrosonornicotine (NNN) was from 28 to 730 ng/cigarette and for 4-(methylnitrosamino)-1-(3-pyridyl-1-butanone (NNK) from 16 to 369 ng/cigarette. The relatively highest TSNA values were obtained in filter and nonfilter cigarettes with high tar (22.3-28.1 mg/cigarette) and high nicotine (1.78-2.42 mg/cigarette) deliveries. The results demonstrated that there is a correlation between TSNA and tar and nicotine deliveries in mainstream smoke. The TSNA deliveries, along with the tar and nicotine levels in mainstream smoke depended on the tobacco composition. According to these results, the tar levels alone, while significant, are not a sufficient measure for the biological activity and the carcinogenic potential of cigarettes in Thailand. Consumption of tobacco products nearly quadrupled over the last three decades (1966-1995) in Thailand. Lung cancer is the leading malignancy for men and a common malignancy for women in Thailand. This report provides information that may prove helpful in evaluating the TSNA-carcinogens burden on smokers. Our goal is to offer the scientific basis for voluntary and/or government-regulated reduction of the smoke yields of TSNA in tobacco products in Thailand and in other countries.

Carcinogens↗
PubMed1996

Immunohistochemical localization of surfactant protein A in N-bis (2-hydroxypropyl) nitrosamine-induced lung tumors in rats.

Surfactant protein A (SP-A) is most abundant protein associated with pulmonary surfactant which is synthesized by alveolar type II cells in the alveoli. In this study, we localized SP-A in experimentally induced pulmonary hyperplasias and tumors in rats, by immunohistochemistry. When rats were given a single intraperitoneal injection of N-bis (2-hydroxypropyl) nitrosamine (BHPN) followed by exposed to mixture gases of O3 and NO2, hyperplastic alveolar type II cells stained with the antibody against SP-A were located in the alveolar walls near the alveolar ducts. Adenomas and adenocarcinomas were stained with the anti-SP-A antibody in the lung parenchyma. These immunohistochemical findings suggested that the lung tumors induced in rats treated with BHPN and additionally exposed to mixture gases of O3 and NO2 are derived from mainly alveolar type II cells.

Animals↗
PubMed1977

Summation effect of N-butyl-n-(4-hydroxybutyl)nitrosamine, N-(4-(5-nitro-2-furyl)-2-thiazoly)formamide, N-2-fluoroenylacetamide, and 3,3'-dichlorobenzidine on urinary bladder carcinogenesis in rats.

The effects of the sequential administration of 0.01% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), 0.15% N-(4-(5-nitro-2-furyl)-2-thiazoly)formamide (FANFT), 0.025% N-2-fluorenylacetamide (2-FAA), and 0.3% 3.3'-dichlorobenzidine (3,3'-DCB) on urinary bladder carcinogenesis were examined in male Wistar rats. Each chemical was administered for 4 weeks in various combinations. BBN for 4 weeks resulted in no histopathological changes, mild diffuse cell growth, and/or focal hyperplasia after 4, 8, 12, or 16 weeks of observation. No bladder carcinomas were present in rats given only BBN or any one of the other 3 chemicals. Statistically significant incidences of bladder carcinomas occurred with the sequential administration of all 4 chemicals or the first 3 chemicals without 3,3'-DCB. Bladder cancer was also present in rats administered the sequence of FANFT, 2-FAA, and 3,3'-DCB. No antagonistic effects between chemicals were observed.

2-Acetylaminofluorene↗
PubMed1977

Metabolism of three cyclic nitrosamines in Sprague-Dawley rats.

The metabolism of three cyclic nitrosamines has been studied in Sprague-Dawley rats. The compounds were nitrosopyrrolidine, nitrosohexamethyleneimine, and nitrosohepatamethyleneimine and were labeled at the alpha carbon with 14C. At low doses (2 to 4 mg/animal) the compounds were metabolized to 14CO2 to the extent of 77, 43, and 27%, respectively, after 24 hr. At doses closer to the 50% lethal dose of the compounds (70 to 160 mg/animal) the metabolism values were only 14, 4, and 8%, respectively, after 24 hr. The significance of these results is discussed.

Air↗
PubMed1996

[Occupational exposure to n-nitrosamine in the production of automobile tires].

Applying the method for determining nitrocompounds, based on gaz chromatography technique with nitro-phosphoric detector, N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodibutylamine, N-nitrosotetrahydropyrrole were detected in the work environment of the plant under study (method of determining 0.2 micrograms/m3 for 1000 l/air). For qualitative purposes the data obtained were supported by mass spectrometry. Measurements of individual exposure were taken in 35 persons and stationary measurements were also applied. Among nitrosamines detected, N-nitrosodimethylamine (carcinogenic substance) occurred most commonly at working post, and its concentration was the highest (2.1-9.2 micrograms/m3).

Automobiles↗
PubMedDate not supplied

Effects of orally administered capsaicin, the principal component of capsicum fruits, on the in vitro metabolism of the tobacco-specific nitrosamine NNK in hamster lung and liver microsomes.

Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the principal component in Capsicum fruits consumed worldwide as a food additive. Capsaicin is known for its hot, pungent qualities. The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is viewed as an important etiological factor in the causation of human lung cancer. In our study, a single oral dose of capsaicin administered by oral gavage at 2 mg/kg and 10 mg/kg body weight to male Syrian golden hamsters altered the in vitro metabolism of NNK by liver and lung microsomes. The most significant effect was on the inhibition of alpha-carbon hydroxylation. The orally administered capsaicin inhibited the formation of keto aldehyde (methylating pathway) and the formation of keto alcohol (pyridyloxobutylating pathway) in lung microsomes except for microsomes from animals receiving 10 mg/kg capsaicin 24 h post-treatment. In contrast, capsaicin inhibited only the methylating pathway in liver microsomal metabolism of NNK. This effect persisted at 24 h post-treatment. Since it is reported that the pyridyloxobutylating pathway enhances the effects of the more damaging methylating pathway in the metabolism of NNK (reference 25), our results suggest that any potentially chemopreventive action of orally administered capsaicin may be greater toward NNK-induced lung tumorigenesis than toward NNK-induced liver tumorigenesis.

Administration, Oral↗
PubMed1977

Nitrites, nitrosamines, and meat.

Food additive regulations are frequently misunderstood and are often the basis for widely disparate views. The US Department of Agriculture (USDA) does not accept the concept that zero health risk with food additives is a humanly attainable goal; however, if the USDA is to accept that zero health risk is not attainable, then the department must propose, through regulations, a socially acceptable level of risk. Nitrite is an example. On one hand, nitrite is toxic at high levels and can combine with amines to form nitrosamines, which have been shown to cause cancer in animals. On the other hand, nitrite has been shown to provide the necessary protection, in many products, against Clostridium botulinum. The USDA, however, is not content to accept this position as a final one; they will continue to urge additional studies designed to further refine and decrease nitrite usage or replace it with a safe substitute. Given adequate information as to the relative risks involved in the use of nitrite or a substitute, society itself should be in a position to make the determination as to its willingness to accept potential risks in its daily life.

Animals↗
PubMedDate not supplied

[Hygienic aspects of the study of the synthesis of nitrosamines from their precursors].

The paper presents data on the content of nitrosamines (NA), such an nitrosodimethylamine, nitrosodiethylamine, and their precursors (NO2 and amines) in the ambient air of different functional zones of a city. A high correlation between NA and NO2 in the air was established. NO2 was shown to have the leading role as a nitrosating agent in the model system and air during exogenous synthesis. The findings support the possible endogenous production and the role of NO2 in this process.

Air Pollutants↗
PubMedDate not supplied

[Nitrogen dioxide in the environmental air as a precursor of endogenous synthesis of carcinogenic nitrosamines].

The experiment was conducted on white noninbred rats receiving different concentrations of the nitrosamine (NA) precursors NO2 and amidopyrinum. Carcinogenic NAs were determined in the organs of the animals that had inhaled them at concentrations of 0.4, 0.8, and 4.0 mg/m3. There was an increase in tumors in chronic experiments on exposure to NA in the same doses as compared with the controls. It was found that the ambient air NO2 level of 0.4 mg/m3 (MAC 10 mg/m3) should be considered to be hazardous due to the fact that there might be exogenous and endogenous syntheses and that the NA might exert a carcinogenic effect.

Animals↗
PubMedDate not supplied

[Gas chromatographic analysis of volatile nitrogen bases in boiled beef; possible N-nitrosamine precursors].

The composition of nitrogen-containing organic bases in the volatile substances of boiled beef has been studied. For the first time 30 compounds have been identified, including primary, secondary, and tertiary aliphatic amines, pyrazines, pyridine, piperidine and their alkyl substituted derivatives. The content of trimethyl-, diethyl-, diisopropyl-amines, and piperidine, possible precursors of N-nitrosamines, has been quantitated.

Amines↗
PubMed1998

11Beta-hydroxysteroid dehydrogenase responsible for carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in mouse lung microsomes.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent pulmonary carcinogen in laboratory animals and is most likely involved in the etiology of tobacco smoke-induced lung cancer. To exert its carcinogenic potential, NNK must be metabolically activated by alpha-hydroxylation at either the methyl or methylene carbons adjacent to the N-nitroso group. The main detoxification pathway of NNK involves carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol followed by glucuronosylation at the hydroxy moiety produced by carbonyl reduction. Whereas there has been great success in the identification of cytochrome P450 species catalyzing NNK activation, the enzyme responsible for NNK carbonyl reduction has been searched for since 1980. In previous investigations, we succeeded in identifying the NNK carbonyl reducing enzyme in mouse liver microsomes as being 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD 1; EC 1.1.1.146), an enzyme that is physiologically involved in glucocorticoid oxidoreduction. In this study, the expression of 11beta-HSD 1 was established on the mRNA (reverse transcription-PCR) and protein (immunoblot) levels. Kinetics of glucocorticoid oxidoreduction were determined with corticosterone and dehydrocorticosterone as substrates for oxidation and reduction, respectively. The apparent Vmax (135.8 versus 48.1 pmol/min/mg of protein) and Km (6.8 versus 35.8 microM) values were much in favor for corticosterone oxidation compared to dehydrocorticosterone reduction. NNK carbonyl reduction displayed an apparent Vmax of 655 pmol/min/mg of protein and a Km of 629 microM. Interestingly, the intrinsic clearance (Vmax/Km ratio) of NNK carbonyl reduction (1.04) corresponds roughly to that of glucocorticoid reduction (1.34). The physiological glucocorticoid substrates of 11beta-HSD 1 (corticosterone and dehydrocorticosterone) and the selective 11beta-HSD 1 inhibitor glycyrrhetinic acid turned out to be strong inhibitors of NNK carbonyl reduction, displaying Ki values of 37.8, 21.3, and 10.9 microM, respectively. Affinity-purified antibodies specific for mouse liver 11beta-HSD 1 inhibited NNK carbonyl reduction in a concentration-dependent manner. For example, at the highest antibody concentration (5 microg of protein), 11beta-HSD 1 activity was decreased to a residual 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol formation of only 7.9% compared to the uninhibited control, thus conclusively demonstrating NNK carbonyl reduction to be mediated by 11beta-HSD 1 in mouse lung microsomes. Evidence is provided in the present study that 11beta-HSD 1 is expressed in mouse lung and that it functions as NNK carbonyl reductase in mouse lung microsomes. These findings may have potentially important implications for smokers who express low levels of 11beta-HSD 1/NNK carbonyl reductase and/or are concurrently being exposed to 11beta-HSD 1 modulators.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

[Nitrosamines].

The paper reviews data on the property and mechanism of toxicologic effects of nitrosamines. Particular attention is turned to metabolism and carcinogenesis of these compounds in view of their concentration in human environment.

Animals↗