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PubMed1987

Demonstration of in vivo formation of the nitrosamine N-nitroso-N-methylaniline from amyl nitrite.

Kaposi's sarcoma is associated with Acquired Immune Deficiency Syndrome (AIDS) in U.S. homosexuals. A possible explanation is that butyl nitrite, inhaled as a drug of abuse, initiates the tumor via the in vivo formation of N-nitroso compounds. To demonstrate that such a process can occur, we injected mice i.p. with the amine N-methylaniline (250 mg/kg), gavaged them 30 min later with amyl nitrite (AmNO2, 40 mg/kg), killed the mice after another 30 or 60 min, and analyzed the carcasses for N-nitroso-N-methylaniline (NMA). We obtained 480 +/- 130 (mean +/- S.E. for 6 mice killed after 30 min) and 380 +/- 40 (for 6 mice killed after 60 min) nmol NMA/mouse. Much lower yields were obtained when AmNO2 was injected i.p. and methylaniline was gavaged. Hence, relatively large amounts of at least one nitrosamine can be produced in vivo from simple nitrite esters.

Amyl Nitrite↗

PubMed1987

Tumorigenic activity of the tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL) and N'-nitrosonornicotine (NNN) on topical application to Sencar mice.

The tumor-initiating activities of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL) and N'-nitrosonornicotine (NNN) were evaluated on the skin of female SENCAR mice. A total initiator dose of 28 mumol/mouse of each nitrosamine was applied in 10 subdoses administered every second day. Promotion commenced 10 days after the last initiator dose and consisted of twice weekly application of 2.0 micrograms of tetradecanoylphorbol acetate for 20 weeks. NNK induced a 79% incidence of skin tumors with an average of 1.6 tumors/mouse and a 59% incidence of lung adenomas. In contrast, iso-NNAL and NNN were not active as tumor initiators in either the skin or lung of mice. The tumorigenic activity of NNK on SENCAR mouse skin was evaluated at several doses. At a total initiator dose of 28 and 5.6 mumol/mouse, NNK exhibited significant activity (P less than 0.005) inducing a 59% and 24% incidence of skin tumors, respectively. In this dose response bioassay, NNK at a total initiator dose of 28 mumol induced a 63% incidence (P less than 0.005) of lung adenomas. The numbers of lung adenomas induced at the lower doses employed were not significant. NNK, at a total initiation dose of 1.4 mumol, did not exhibit significant tumorigenic activity (P greater than 0.05). Analysis of DNA from the skin of mice treated with NNK using HPLC with fluorescence detection failed to detect O6- and N-methylguanine (O6-MG and N7-MG) adducts. These data indicate that NNK can exert a contact carcinogenic effect and suggest that mechanisms other than DNA methylation may be involved in its activation to a tumorigenic agent in mouse skin.

Administration, Topical↗

PubMed1988

Promotive effect of 4,4'-methylenebis(N,N-dimethyl)benzenamine on N-bis(2-hydroxypropyl)nitrosamine-induced thyroid tumors in Wistar rats.

The promotive effect of 4,4'-methylenebis(N,N-dimethyl)benzenamine (MDBA) on 2-stage thyroid tumorigenesis induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) in Wistar male rats was investigated. Animals were given i.p. injections of DHPN, and then a basal diet containing 0.0375% MDBA for 19 weeks. In addition, localization of the thyroid-stimulating hormone (TSH) in the pituitary gland was investigated. Levels of TSH and T4 in serum were measured by radioimmunoassay (RIA). The addition of MDBA to the diet significantly increased the incidence and numbers of preneoplastic lesion (focal hyperplasia), adenoma and carcinoma of the thyroid. TSH was usually localized in the thyroidectomy-cell in the anterior lobe of the pituitary gland, and the number of TSH-positive cells increased in the group treated with MDBA. Mean circulating levels of TSH were elevated in all MDBA-treated groups, and mean T4 levels in groups treated with MDBA were significantly lower different (P less than 0.05) than those in control groups.

Aniline Compounds↗

PubMed1988

Effects of trisodium nitrilotriacetate monohydrate, nitrilotriacetic acid and ammonium chloride on urinary bladder carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl) nitrosamine.

The effects of trisodium nitrilotriacetate monohydrate (Na3 NTA.H2O) nitrilotriacetic acid (H3NTA) and ammonium chloride (NH4Cl) on two-stage urinary bladder carcinogenesis were examined. Carcinogenesis was initiated by administration of 0.2% N-bis (2-hydroxypropyl)-nitrosamine (DHPN) to male Wistar rats in the drinking water for 2 weeks, and then the animals were treated with basal diet containing Na3NTA.H2O, Na3NTA.H2O plus NH4Cl, H3NTA, H3NTA plus NH4Cl, or without these chemicals for 28 weeks. Na3NTA.H2O increased significantly the resultant incidence of neoplastic and preneoplastic lesions of the urinary bladder. Moreover, treatment with Na3NTA.H2O, without the initiation, itself induced papillary or nodular (PN)-hyperplasia. H3NTA produced only a slight increase in the incidence of preneoplastic urinary bladder lesions (PN-hyperplasia) in rats initiated by DHPN, and this was not statistically significant. Elevation of both pH and sodium ion concentration in the urine were correlated with promotion of tumor development. These data showed that Na3NTA.H2O was more effective than H3NTA with regard to promoting potential, and that changes in both urinary pH and concentration of sodium played important roles in enhancement of urinary bladder tumorigenesis by these chemicals.

Acetates↗

PubMed1989

Greater inhibitory effects for testosterone than castration in rat thyroid tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine.

The effects of testosterone and castration on thyroid tumorigenesis subsequent to initiation by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were investigated in male Wistar rats. Following 2 weekly i.p. injections of DHPN at the dose of 210 mg/100 g body weight, testosterone was administered in the diet at concentrations of 0.15% or 0.03% for 28 weeks. Castration was performed on a separate group of animals 1 week after the final injection of DHPN. The incidence of thyroid adenomas and carcinomas were 69% (9/13) and 15% (2/13), respectively, in rats treated with DHPN alone, 0% (0/15) and 6% (1/15) in rats treated with DHPN and 0.15% testosterone, 13% (2/15) and 13% (2/15) in rats treated with DHPN and 0.03% testosterone and 33% (5/15) and 33% (5/15) in the castrated animals initiated by DHPN. The reduction in adenoma development associated with testosterone treatment was significant at both concentrations. In contrast, only a tendency for decrease of thyroid tumor incidence was observed in rats castrated.

Animals↗

PubMed1990

Dose response of N-butyl-N-(4-hydroxybutyl)nitrosamine on urinary bladder carcinogenesis in mutant ODS rats lacking L-ascorbic acid synthesizing ability.

With a daily intake of 250 ppm total ascorbic acid, ODS and F344 male rats were given 0.0125%, 0.025% or 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 12 weeks, and additional groups received 0.05% BBN for 2, 4 or 8 weeks. The experiment was terminated after a total of 36 weeks. A greater response to urinary bladder carcinogenesis was observed in both strains with increasing dose of BBN or longer treatment period. However, the magnitude of urinary bladder carcinogenesis in ODS rats given the higher BBN concentrations and/or long periods of BBN treatment was less than in comparably treated F344 rats, but not with lower concentrations of BBN and/or shorter periods of BBN treatment.

Animals↗

PubMed1991

Potential of endogenous formation of volatile nitrosamines from Nigerian vegetables and spices.

Nitrosatability of dried Nigerian vegetables and spices was investigated under simulated gastric conditions. N-Nitroso-dimethylamine (NDMA) was the only volatile nitrosamine found above the preformed level except in ugwu where N-nitroso-piperidine (2.3 ppb) was also detected. The lowest NDMA value of 0.4 ppb was found in bitterleaf while onions had the highest level (14.7 ppb) of nitrosation. The results suggest that, under endogenous conditions, nitrosation of these foodstuffs could be an important contributory factor in cancer aetiology.

Food Preservation↗

PubMed1994

Ki-ras oncogene activation in transplantable rat thyroid carcinoma induced by N-bis(2-hydroxypropyl)nitrosamine.

We have established 17 transplantable rat thyroid carcinoma cell lines from primary thyroid tumors of rats induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) (Cancer Res. (1993) 53, 4408-4412). The present study was designed to evaluate point mutations in the murine c-Ki-ras gene of these carcinoma cell lines. Using PCR amplification and direct sequencing, we found that the activated form of the Ki-ras oncogene was present in 4 (23%) of a total of 17 cell lines, all the Ki-ras gene mutations being GC-->AT transitions. In three of the cell lines, the mutations occurred in codon 12 (GTP-binding domain), and in the remaining one the first nucleotide of codon 63 was affected. Histologically, three of the carcinomas with Ki-ras mutation were diagnosed as well-differentiated carcinomas, and the other as poorly differentiated carcinoma. Mutations of the ras gene are relatively uncommon in tumors of these histological types. From these experimental results, we suggest that the mutation induced by DHPN is due to damage to guanine in cellular DNA. In addition, Ki-ras activation may play an important role in the initiation of thyroid carcinogenesis.

Animals↗

PubMed1995

Frequent mutations of Ki-ras codon 12 in N-bis (2-hydroxypropyl)-nitrosamine-initiated thyroid, kidney and lung tumors in Wistar rats.

N-Bis (2-hydroxypropyl) nitrosamine (DHPN) is a very potent mutagen and wide spectrum carcinogen in rodents. In the present study, we investigated mutational activation of the Ki-ras gene in eight thyroid, five kidney (four mesenchymal and one transitional cell lesion) and two lung tumors induced with DHPN. Mutations were identified using single-strand conformation polymorphism, restriction fragment length polymorphism and DNA sequencing analysis. All of the 15 neoplasms could be shown to have mutations in codon 12 (GGT-->GAT). These results suggest that Ki-ras mutations are frequent events during the development of DHPN-induced carcinomas in these organs. In a separate experiment, moreover, we analyzed the presence of Ki-ras mutations in various tissues 8 weeks after DHPN treatment. One of five thyroid tissues treated with DHPN was found to have the same characteristic mutation, suggesting that it may represent an early event during carcinogen-induced tumor formation in the thyroid.

Animals↗

PubMed1995

Tobacco-specific nitrosamines in some Nigerian cigarettes.

Ten popular brands of cigarettes on the Nigerian market were analyzed for tobacco-specific nitrosamines (TSNA) in tobacco and in mainstream smoke, as well as nitrate in tobacco. TSNA was analyzed using a gas chromatography/thermal energy analyzer (GC-TEA), while nitrate was determined spectrophotometrically as nitrite following on-line reduction with copper, diozatization with sulfanilamide and coupling with N-(1-naphthyl) ethylene diamine to form an azo dye. In mainstream smoke, the concentration of NNN, NAB/NAT and NNK were respectively, between 8 and 90 ng, 10 and 65 ng, and between 15 and 72 ng/cigarette. Preformed NNN ranged between 64 and 565 ng/cigarette, while preformed NAB/NAT and NNK ranged respectively from 109 to 476 ng/cigarette, and from 55 to 317 ng/cigarette. Nitrate levels ranged between 1.5 and 6.1 mg/g tobacco. In general, the results indicate that the TSNA content of Nigerian cigarettes are within the range found for European and American cigarettes.

Nicotine↗

PubMed1994

Nitrosamine formation via non-prescription drugs?

Both carcinogenic and non-carcinogenic nitrosamines can be formed under physiological conditions in the human body by a reaction between nitrite and secondary or tertiary amines. A large number of people are exposed daily through drinking water to high levels of nitrate, which can be reduced to nitrite. Moreover, nitrate and nitrite are present in vegetables and nitrite is used in food preservation. Dietary exposure to amines is normally below 100 mg per day, whereas paracetamol and antazolin, 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↗

PubMed1988

Effects of urinary crystals induced by acetazolamide, uracil, and diethylene glycol on urinary bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated rats.

In order to examine the promoting effect of urinary crystals on urinary bladder carcinogenesis, acetazolamide, uracil, and diethylene glycol, all of which have been reported to cause urinary crystals or calculi, were administered to male F344 rats for 32 weeks after pretreatment with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks. A marked increase in urinary crystals was observed in acetazolamide-treated rats and a slight increase in crystals was observed in uracil- and diethylene glycol-treated rats. Histological examination of the urinary bladder revealed that the BBN-acetazolamide treatment resulted in a higher incidence of carcinoma than BBN-control. Uracil and diethylene glycol did not cause any significant difference compared to the control. Promoting effects by urinary crystals were not clearly shown in the present experiment and, therefore, urinary crystals appear to play a very limited role, if any, in urinary bladder carcinogenesis.

Acetazolamide↗

PubMed2004

Lack of prepubertal administration of ethinyl estradiol on susceptibility to multiple organ carcinogenesis in rats exposed to 7,12-dimethylbenz[a]anthracene and N-bis(2-hydroxypropyl)nitrosamine during adolescence.

Estrogen exposure during the adult period is widely known to promote tumor development in the female genital system, as well as in the mammary gland in experimental animals, but its carcinogenic potential with exposure at the prepubertal stage, for 6 weeks after birth, is not completely understood. In the present study, we therefore evaluated the modifying effects of prepubertal ethinyl estradiol (EE) treatment on susceptibility to multiple organ carcinogenesis with subsequent carcinogen exposure in F344 rats. Dams during the lactation period and their weaned offspring until postnatal-week 6 were fed diet containing 0, 0.2 or 1.0 ppm EE. The offsprings were then administered 7,12-dimethylbenz[a]anthracene (DMBA, 50mg/kg body weight) by gavage for mammary tumor induction in week 7 and given free access to drinking water containing N-bis (2-hydroxypropyl)nitrosamine (DHPN, 0.2%) for wide spectrum tumor induction in organs such as the thyroid, liver, lung and kidney from weeks 6-14. Male and female offspring were euthanized at weeks 27 and 36, respectively, for histopathological examination. While the incidence and multiplicity of mammary tumors showed a tendency for increase in females of the 0.2 and 1.0 ppm EE groups, this was without statistical significance. Furthermore, prepubertal EE exposure did not affect tumor induction in the thyroid, liver, lung, kidney, esophagus, ovary and lymphoid tissue in either sex. The present results thus indicate a lack of influence of estrogen early in life on carcinogenic susceptibility, although the possible impact on mammary carcinogenesis requires further examination.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Organ-specific susceptibility of p53 knockout mice to N-bis(2-hydroxypropyl)nitrosamine carcinogenesis.

To elucidate which is the major determinant of susceptibility of p53 deficient mice, the carcinogen or the target organ, N-bis(2-hydroxypropyl)nitrosamine was administered to induce tumors in multi-organs. In a 15-week experiment, the incidences of both lung and hepatic vascular tumors were found to be significantly higher in p53 nullizygous (-/-) than in heterozygous (+/-) and wild-type (+/+) mice, indicating universal susceptibility of p53 (-/-) mice. In a 40-week experiment, p53 (+/-) mice showed increased susceptibility only with regard to vascular tumors, coinciding with significantly more frequent (60%) p53 gene mutations, in comparison with lung tumors with their low mutation rate (10.8%) (P<0.005). These results indicate that the target organ may be a more important factor than the carcinogen in determining susceptibility of p53 (+/-) mice.

Animals↗

PubMed2005

Adsorption of nitrosamines in acidic solution by zeolites.

Adsorption of N-nitrosopyrrolidine (NPYR) by zeolite NaZSM-5, Hbeta and NaZSM-11 in acidic solution with pH of 1 was investigated. The NPYR uptake process obeyed the first-rate Lagegren kinetic equation describing adsorption, and the equilibrium data were fitted to the Langmuir or Freundlich adsorption equation. Zeolite ZSM-5, Hbeta and NaZSM-11 possessed a higher adsorption capacity than amorphous silica or ordered mesoporous siliceous SBA-15, implying their potential application for adsorption of nitrosamines in gastric juice to anti-cancer.

Adsorption↗

PubMed2006

Solid-phase microextraction of N-nitrosamines.

A method was developed for the extraction of seven N-nitrosamine compounds from water by solid-phase microextraction (SPME). The method developed requires a total analysis time of only 1.25 h for both extraction and detection (versus 3-20 h for other isolation techniques). Three gas chromatography (GC) detection systems were tested with the SPME method, nitrogen chemiluminesence detection (NCD), nitrogen-phosphorus detection (NPD) and chemical ionization mass spectrometry (CI-MS), with method detection limits (MDLs) found in the ng/L range. This method was used to analyze wastewater samples and showed excellent selectivity of extraction. The detection limits of this method for N-nitrosodimethylamine (NDMA) range from 30 to 890 ng/L as a function of detector type. The excellent selectivity of SPME in addition to the fast analysis time would make this method ideal for general surveys, wastewater analysis and laboratory studies (e.g. degradation kinetics or formation potential).

Chromatography, Gas↗

PubMed2006

Effect of a flue-curing process that reduces tobacco specific nitrosamines on the tumor promotion in SENCAR mice by cigarette smoke condensate.

A 30-week dermal tumor promotion study was conducted to evaluate the dermal tumor-promoting potential of cigarette smoke condensate (CSC) collected from cigarettes containing flue-cured tobacco cured by a heat-exchange process (HE) relative to that of cigarettes containing flue-cured tobacco cured by the traditional direct-fire process (DF). Heat-exchange process cured tobacco contains significantly lower concentrations of tobacco specific nitrosamines (TSNAs) compared to traditional direct-fire cured tobacco. Mainstream CSCs were collected by cold trap from smoke generators using the Federal Trade Commission puffing regimen. Groups of 40 female SENCAR mice were initiated by a single application of 75 micro g 7,12-dimethylbenz[a]anthracene (DMBA) to the shaved dorsal skin. CSCs were then applied to the skin three times/week for 29 weeks at 9, 18, or 36mg tar/application. End-points included body weights, clinical observations, organ weights, dermal tumor development and histopathology. The numbers of dermal tumors and the numbers of tumor-bearing mice for each CSC were statistically different from the DMBA/acetone control group and increased with increasing dose. When corresponding doses of each CSC were compared, only the DMBA/mid-dose HE CSC group was statistically significantly different (lower) from the corresponding DMBA/mid-dose DF CSC group. In this assay, the dermal tumor-promotion potential of CSC from heat-exchange flue-cured tobacco did not differ from that of traditional direct-fire flue-cured tobacco CSC.

Administration, Cutaneous↗

PubMed2005

The reaction of flavanols with nitrous acid protects against N-nitrosamine formation and leads to the formation of nitroso derivatives which inhibit cancer cell growth.

Studies have suggested that diets rich in polyphenols such as flavonoids may lead to a reduced risk of gastrointestinal cancers. We demonstrate the ability of monomeric and dimeric flavanols to scavenge reactive nitrogen species derived from nitrous acid. Both epicatechin and dimer B2 (epicatechin dimer) inhibited nitrous acid-induced formation of 3-nitrotyrosine and the formation of the carcinogenic N-nitrosamine, N-nitrosodimethylamine. The reaction of monomeric and dimeric epicatechin with nitrous acid led to the formation of mono- and di-nitroso flavanols, whereas the reaction with hesperetin resulted primarily in the formation of nitrated products. Although, epicatechin was transferred across the jejunum of the small intestine yielding metabolites, its nitroso form was not absorbed. Dimer B2 but not epicatechin monomer inhibited the proliferation of, and triggered apoptosis in, Caco-2 cells. The latter was accompanied by caspase-3 activation and reductions in Akt phosphorylation, suggesting activation of apoptosis via inhibition of prosurvival signaling. Furthermore, the dinitroso derivative of dimer B2, and to a lesser extent the dinitroso-epicatechin, also induced significant toxic effects in Caco-2 cells. The inhibitory effects on cellular proliferation were paralleled by early inhibition of ERK 1/2 phosphorylation and later reductions in cyclin D1 levels, indicating modulation of cell cycle regulation in Caco-2 cells. These effects highlight multiple routes in which dietary derived flavanols may exert beneficial effects in the gastrointestinal tract.

Absorption↗