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PubMed1992

In vivo and in vitro genotoxicity of several N-nitrosamines in extrahepatic tissues of the rat.

Toxicological mechanisms involved in organotropism of tumor induction may include cell-specific metabolic activation of the carcinogen, in vivo distribution of active metabolites and persistance of induced DNA damage. In order to elucidate which factors are involved in the organotropic action of environmentally relevant N-nitrosamines, we have studied their genotoxic and cytotoxic effects within primary intact cells of lung and kidney. The end-points determined were cytotoxicity by trypan blue exclusion and DNA single-strand break (SSB) induction by alkaline filter elution. The assays were performed in vitro to determine organ-specific metabolic activation by incubating the cells with the test compounds. The results obtained with N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiethanolamine (NDEIA), N-nitrosoethylvinylamine (NEVA), N-nitrosodibutylamine (NDBA), N-nitrosobutylbutanolamine (NBBOH), N-nitrosobutylcarboxypropylamine (BCPN), N-nitrosomethylbenzylamine (NMBzA) and N-nitrosodibenzylamine (NDBzA) indicate that several compounds may be activated to reactive metabolites by cells of kidney and lung, NDBzA revealing the highest degree of cytotoxicity. In contrast, genotoxicity in kidney cells was induced only by NBBOH and BCPN and at relative low levels. Primary lung cells could not be employed as indicators for genotoxic effects in vitro because the cell yield was not sufficient to perform the alkaline elution assay. To assess the distribution of NDMA in the whole rat and the persistence of the induced DNA damage in the two organs, further studies were carried out after oral application of 1, 2, 4, 10, 20, 32 and 40 mg/kg to the animals. Following 1 h exposure of rats to NDMA, the lowest effective genotoxic dose for lung and kidney was 2 mg NDMA/kg body wt. A plateau was achieved after a dose of 20 mg/kg in both organs. Furthermore, the persistence of DNA damage was studied in the lung. After 4 h exposure, DNA damage was still detectable at 32 mg NDMA/kg, but for the lower doses it was reduced nearly to control levels. After 16 h exposure the SSB rate in lung cells was reduced for all dose levels except for the highest dose of 40 mg/kg.

Animals↗
PubMed1992

Bioavailability of tobacco-specific N-nitrosamines to the snuff dipper.

Use of supercritical carbon dioxide extraction in the analysis of smokeless tobacco for tobacco-specific N-nitrosamines revealed the presence of higher levels of 4-(methylnitros-amino)-1-(3-pyridyl)-1-butanone (NNK) than had been determined with conventional methods. Whether human saliva may be similarly capable of releasing apparently bound NNK during chewing or snuff dipping was tested by incubating smokeless tobacco with enzymatically active saliva and with heat-treated saliva respectively. Enzymatically active human saliva was found to liberate up to twice the amount of the highly carcinogenic NNK than did heat-treated saliva. This is of major consequence for the cancer risk assessment of snuff dippers and tobacco chewers.

Biological Availability↗
PubMed1992

Carcinogenic tobacco-specific nitrosamines are present at unusually high levels in the saliva of oral snuff users in Sudan.

Exposure to tobacco-specific nitrosamines (TSNA) has been measured in the saliva of 12 users of Sudanese oral snuff (toombak). Using GC coupled to thermal energy analysis, levels of N'-nitrosonornicotine (NNN), N'-nitrosoanatabine (NAT), N'-nitrosoanabasine (NAB) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were measured before, during and after snuff taking. In addition, two TSNA, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and 4-(methylnitrosamino)-4-(3-pyridyl)-1-butanol (iso-NNAL), were detected in the saliva of tobacco chewers for the first time and were confirmed by GC-MS. Nine out of 10 subjects had detectable saliva levels of total TSNA before chewing (0.01-1.0 micrograms/ml) and immediately following chewing (0.1-2.6 micrograms/ml). During dipping, TSNA concentrations reached microgram/ml levels; (range; number of subjects positive) NNN: (0.6-2.1; 12/12), NAT (0.06-0.5; 2/12), NAB (0.05-1.9; 12/12), NNK (0.06-6.7; 11/12), NNAL (0.05-3.3; 11/12) and iso-NNAL (0.07-0.4; 8/12). These saliva TSNA levels, which are 10-100 times the levels previously reported, are consistent with recent observations of unusually high TSNA levels in Sudanese toombak. As several of these TSNA have been shown to be carcinogenic in animals and epidemiological studies have associated human snuff use with tumours of the oral cavity, these findings draw attention to a significant potential public health hazard.

Adolescent↗
PubMed1993

Increased endogenous N-nitrosamine and nitrate formation by induction of nitric oxide synthase in rats with acute hepatic injury caused by Propionibacterium acnes and lipopolysaccharide administration.

In rats treated i.v. with heat-killed Propionibacterium acnes (100 mg/kg body wt), followed 5 days later by an i.v. dose of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt), acute hepatic cell necrosis was accompanied by significant induction of nitric oxide (NO) synthase activity in the liver. Endogenous nitrosation of thiazolidine 4-carboxylic acid (TCA, 50 mumol/rat) administered by three different routes (i.v., i.p. and p.o.) 5 h after LPS injection to the P. acnes-treated rats was assessed by analysing its nitrosated product (NTCA) excreted in 24 h urine. The amounts of NTCA formed in vivo after i.v., i.p. and p.o. administration of TCA were 4.07 +/- 1.00, 5.79 +/- 2.15 and 58.3 +/- 20.7 nmol/rat (n = 5-10) respectively, which were about 5-, 10- and 8-fold greater than those excreted by rats which had not been treated with P.acnes and LPS but received TCA by the same route. Nitrate concentration in plasma and NO synthase activity in the liver started to increase within 2.5 h after LPS injection, reached a maximum at 7.5 h and remained at high levels for several further hours. Levels of nitrite and nitrate in gastric contents were also increased significantly after LPS administration. The co-administration of N omega-nitro-L-arginine (an inhibitor of NO synthase) and LPS resulted in a marked reduction of urinary levels of nitrate and NTCA, indicating that nitrosation is mediated by NO synthase. These results together suggest that induction of NO synthase by infection with bacteria, parasite and viruses could result in increased endogenous nitrosation not only in the infected tissues but also in the stomach, where nitrosamines would be formed more rapidly under acidic conditions.

Amino Acid Oxidoreductases↗
PubMed1993

Regressive and non-regressive thyroid lesions of the rat induced by single injection of N-bis(2-hydroxypropyl)nitrosamine and iodine deficient diet.

Six-week-old male F344 rats were divided into 4 groups. Rats in Groups 1 (n = 16) and 3 (n = 14) received a s.c. injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN) (2800 mg/kg) in experimental week 1 while rats in Groups 2 (n = 5) and 4 (n = 5) received saline. From weeks 2-20, all rats were given an iodine deficient (I-def) diet and tap water. Groups 1 and 2 were killed for the measurements of thyroid-stimulating hormone (TSH), thyroxine (T4), the maximum thyroid width (MTW), thyroid weight, morphology, morphometrics and proliferating cell nuclear antigen (PCNA) labeling index (LI). The thyroids of the rats in Group 3 and 4 were surgically exposed and the MTWs were measured. These latter rats were given basal diet for 6 weeks to recover from iodine deficiency, and then killed for the same measurements. Thyroid nodular lesions in Group 1 rats were classified into five categories (NL0, NL1, NL2, NL3 and NL4) based upon incremental cellular and structural atypia. Two types of regressive nodules (NL'0 and NL'1+2) were identified in the recovered rats as the regressed form of NL0, NL1 and NL2 lesions. NL3 and NL4 nodules were seen in Groups 1 and 3. The mean number of combined NL0, NL1 or NL2 lesions was 28.44 +/- 6.12 nodules per rat (NPR) in Group 1 rats and the mean number of NL'0 and NL'1+2 lesions was 28.07 +/- 13.05 NPR in Group 3 rats. The mean number of NL3 or NL4 lesions was 1.70 NPR in Group 1 rats and 3.42 NPR in Group 3 rats. The LIs were NL0 (6.4 +/- 2.5%), NL1 (7.7 +/- 4.4%), NL2 (0.7 +/- 0.3%), NL3 (7.5 +/- 1.3%) and NL4 (14.4 +/- 5.3%) in Group 1 rats and NL'0 (< 0.001%), NL'1 + 2 (< 0.01%), NL3 (9.0 +/- 4.4%) and NL4 (23.3 +/- 17.8%) in Group 3 rats. The thyroid weights of Group 4 rats were 41% of Group 2 rats. The volume fraction (VF) of the non-NL3, non-NL4 areas in Group 3 rats was 40% of that in Group 1 rats. However, the VF of NL3 or NL4 lesions in Group 3 rats was 520% of that of Group 1 rats. In summary, the growth of the NL0, NL1 and NL2 lesions was TSH-dependent, whereas NL3 and NL4 lesions were TSH-independent.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Synthesis of nitric oxide and nitrosamine by immortalized woodchuck hepatocytes.

Woodchuck (Marmota monax) hepatic cells, which were immortalized by the simian virus 40 large T antigen (SV40 Tag) produced nitric oxide (NO; measured as nitrite) in vitro from L-arginine (L-Arg) after lipopolysaccharide (LPS) treatment. NO synthesis was related to L-Arg and LPS concentration and plateaued at 1.0 mM L-Arg and 1.0 microgram/ml LPS. LPS-stimulated cells nitrosated morpholine to form N-nitrosomorpholine (NMOR) in the presence of L-Arg at pH 7.4. NMOR production increased 7-fold in LPS stimulated cells compared to unstimulated hepatocytes. N-nitrosodimethylamine (NDMA) was detected in the cell culture medium in the presence of LPS and L-Arg but without added dimethylamine. NG-monomethyl-L-arginine, a selective inhibitor of nitric oxide synthase, inhibited formation of NO and NMOR, indicating that NO and nitrosating agents were formed via the L-Arg-nitric oxide pathway. These data are the first to report NO and N-nitrosamine production by immortalized hepatocytes and confirm earlier work showing that primary hepatocytes form NO in culture. This suggests that hepatic formation of N-nitroso compounds and/or NO could be an etiologic factor in hepatocellular carcinoma. Immortalized woodchuck hepatic cells may be useful as in vitro models to study the L-Arg-nitric oxide pathway and its possible role in liver carcinogenesis.

Animals↗
PubMed1994

Nicotine inhibits the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rats.

The effect of nicotine on the metabolism of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was studied in rats. [1-14C]NNK was s.c. injected at a dose of 0.08 mumol/kg. Co-administration of a 500-fold higher dose of nicotine (40 mumol/kg) did not reduce the overall urinary excretion of radioactivity. However, the metabolic pattern in 24 h urine was significantly changed. Metabolites resulting from NNK activation by alpha-hydroxylation were significantly (P < 0.001) reduced to 72% of the control. Detoxification to N-oxides and the glucuronide of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanol increased to 155% (P < 0.01) and 188% (P < 0.01) of the control respectively. These results suggest that nicotine, which occurs in concentrations up to 30,000-fold higher than NNK in mainstream smoke of cigarettes may have a protective effect against metabolic activation of NNK.

Animals↗
PubMed1996

Variant mutational activation of the K-ras oncogene in renal mesenchymal tumors induced in newborn F344 rats by methyl(methoxymethyl)nitrosamine.

Renal mesenchymal tumors were induced at high incidence in F344 rats by a single intraperitoneal injection of methyl(methoxymethyl)nitrosamine (DMN-OMe) within 48 h after birth. DNAs from 18 of 35 mesenchymal tumors contained transforming ras sequences in NIH3T3 transfection assays: K-ras (17/18) or N-ras (1/18). Single-stranded conformational polymorphism analysis or dideoxy sequencing of polymerase chain reaction-amplified K-ras gene fragments revealed that these neoplasms contained a variety of activating mutations in the K-ras oncogene. Alterations in codon 12 predominated and included GGT --> GAT transitions, GGT --> GTT or TGT transversions, and previously reported insertion mutations, although some tumors expressed more than one mutation and the pattern of mutations even varied within tumors. Mutations were also found in exons 2 and 3. In addition, tumor transplantability into syngeneic hosts correlated positively and significantly with K-ras activation. Renal mesenchymal tumors with transforming mutations in exon 1 were often successfully passaged (10/12) while tumors which lacked mutations in exon 1 were infrequently transplantable (2/14). While the observed base substitutions in K-ras are consistent with adduct formation, the presence of insertion mutations and intratumor heterogeneity of alterations suggest that ras activation in DMN-OMe-induced tumors is not necessarily an early event in tumorigenesis.

Animals↗
PubMed1996

The essential role of the functional group in alkyl isothiocyanates for inhibition of tobacco nitrosamine-induced lung tumorigenesis.

The importance of the isothiocyanate group in alkyl isothiocyanate for inhibition of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3- pyridyl)-1-butanone (NNK)-induce lung tumorigenesis was examined in A/J mice. Our previous structure-activity relationship study of isothiocyanates showed that 1-dodecyl isothiocyanate [CH3(CH2)11NCS], a simple alkyl isothiocyanate, is a potent inhibitor of NNK-induced lung tumorigenesis. It was chosen for this study due to its structural features and potency. A single dose of 1-dodecyl isothiocyanate given by gavage at 1 micromol/mouse 2 h prior to NNK administration completely inhibited lung tumorigenesis, while removal of the isothiocyanate group or replacing it with a hydroxyl group abolished the inhibitory activity. These results demonstrate that the isothiocyanate functional group is critical for the inhibitory activity of isothiocyanates in NNK-induced lung tumorigenesis. To gain more insights into the relationship of in vivo inhibition of tumorigenesis with the cytochrome P-450 enzyme inhibitory activity, the effects of these compounds on metabolism of NNK in mouse lung microsomes were studied. 1-Dodecyl isothiocyanate inhibited all three known oxidative pathways of NNK metabolism, with a stronger inhibitory activity toward NNK N-oxidation (IC50 430 nM) and keto alcohol formation (IC50 500 nM) than keto aldehyde formation (IC50 13,000 nM). 1-Dodecanol had a similar selectivity in inhibition of these metabolic pathways, but was less potent than 1-dodecyl isothiocyanate. Dodecane showed little or no inhibitory activity in the same concentration range. These results indicate that the isothiocyanate group of 1-dodecyl isothiocyanate is important for inhibition of NNK-induced lung tumorigenesis and also for effective inhibition of cytochrome P-450 enzymes involved in NNK oxidation.

Adenoma↗
PubMed1981

Influence of total dose and dose schedule on induction of urinary bladder cancer in the mouse by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Dose-response relationships in the induction of urinary bladder cancer in male C57BL/6 x DBA/2-F1 (BDF) mice by intragastric instillation of N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN) were studied. Administration of a total dose of 0 to 80 mg OH-BBN in 10 weekly fractions to groups of 25 mice resulted in a linear increase in carcinoma incidence with dose. OH-BBN administration schedule had a significant effect on cancer incidence: administration of a total dose of 30, 20, or 15 mg OH-BBN in 20 weekly fractions was more effective in cancer induction than was the same total dose given in 5 fractions. A 10 dose administration schedule was of intermediate efficacy. The data obtained indicate that OH-BBN induces urinary bladder cancers in BDF mice in a dose-related manner, with high target organ-specificity, little toxicity, and short tumor latency; induced tumors are primarily transitional cell carcinomas which morphologically resemble their human counterpart. Administration of OH-BBN mice provides a useful model for the experimental study of urinary bladder cancer.

Animals↗
PubMed1999

Promoting effects of kojic acid due to serum TSH elevation resulting from reduced serum thyroid hormone levels on development of thyroid proliferative lesions in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

In order to examine whether kojic acid (KA) exerts a promoting effect on thyroid carcinogenesis, male F344 rats were initiated with N-bis(2-hydroxypropyl)nitrosamine (BHP; 2800 mg/kg body wt, single s.c. injection) and, starting 1 week later, received pulverized basal diet containing 2 or 0% KA for 12 weeks. Untreated control rats were given basal diet for 13 weeks. As an additional experiment, two groups without BHP initiation received basal diet or diet containing 2% KA for 20 weeks. The serum triiodothyronine (T3) and thyroxine (T4) levels were significantly decreased (half to one-third of values of the BHP alone group) and serum thyroid-stimulating hormone (TSH) was markedly increased (13-19 times higher than the values of the BHP-alone group) in the BHP + KA group at weeks 4 and 12. Similar changes in serum thyroid-related hormones were observed in the group with 2% KA alone at week 4, but not at week 20. Thyroid weights were significantly increased in the BHP + KA and KA-alone groups. Focal thyroid follicular hyperplasias and adenomas were observed in 4/5 and 3/ 5 rats in the BHP + KA group at week 4, respectively. At weeks 12, these lesions were observed in all rats in the BHP + KA group. Animals of the KA alone group showed marked diffuse hypertrophy of follicular epithelial cells at weeks 4 and 20. No changes in thyroid-related hormone levels or thyroid histopathological lesions were observed in either the BHP alone or the untreated control groups. Measurement of liver T4-uridine diphosphate glucuronosyltransferase (UDP-GT) activity at week 4 revealed no significant intergroup differences. These results suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanism independent of T4-UDP-GT activity.

Adenoma↗
PubMed2001

Promoting effects of xylazine on development of thyroid tumors in rats initiated with N-bis(2-hydroxypropyl)nitrosamine and the mechanism of action.

To cast light on whether xylazine hydrochloride (XZ), a veterinary medicine commonly used as a sedative agent for food-producing animals, has any promoting potential for thyroid carcinogenesis, the following studies were performed. In Experiment I, male F344 rats received a diet containing 1000 or 0 p.p.m. XZ for 52 weeks with or without initiation with 2400 mg/kg N:-bis(2-hydroxypropyl)nitrosamine (DHPN). Focal follicular cell hyperplasias, adenomas and/or carcinomas were induced in the DHPN alone, XZ alone and DHPN+XZ groups, and the incidences and multiplicities of these lesions in the DHPN+XZ group were significantly increased as compared with the DHPN alone case. In Experiment II, male F344 rats received a diet containing 1000 or 0 p.p.m. XZ and were examined for serum levels of triiodothyronine (T(3)), thyroxine (T(4)) and thyroid-stimulating hormone (TSH) at weeks 1, 2 and 4. In the XZ group, significant increase in thyroid weight and decrease in serum T(4) levels were observed at all time points. Serum T(3) and TSH levels were significantly decreased and increased, respectively, at week 1, but returned to within the control range thereafter. In Experiment III, male F344 rats received a diet containing 1000 or 0 p.p.m. XZ, they were examined for thyroid iodine uptake and organification of XZ after 1 and 2 weeks. The thyroidal iodine uptake per milligram of thyroid and the amount of iodine bound to 1 mg protein showed a tendency for decrease at week 1 and significant decrease at week 2. These results indicate that XZ has tumor-promoting effects on thyroid follicular cells, and suggest an involvement of alterations in thyroid-related hormone levels due to inhibition of thyroid iodine uptake and organification, resulting, provably, in serum TSH stimulation depending on continuous reduction of serum T(4) level through the feedback system in the pituitary-thyroid axis.

Adenoma↗
PubMed1982

Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine.

Phenobarbital (PB) and barbital (BB) promoted the development of thyroid tumors in rats treated with a sub-effective dose of N-bis(2-hydroxypropyl)nitrosamine (DHPN) for thyroid tumorigenesis. Rats were given s.c. injections of 70 mg DHPN/100 g body weight once a week for 4 or 6 weeks with or without diet containing 500 p.p.m. PB or BB for the next 12 weeks. The incidences of thyroid tumors at the end of week 20 of the experiment were 66% in rats given DHPN for 4 weeks and then PB, 23% in rats given DHPN for 4 weeks and then BB, 100% in rats given DHPN for 6 weeks and then PB, 45% in rats given DHPN for 6 weeks and then BB, and 23% in rats given DHPN for 6 weeks. Rats given only DHPN for 4 weeks or only PB or BB had no thyroid tumors after 20 weeks.

Animals↗
PubMed1982

Fluoro-substituted N-nitrosamines. 2. Metabolism of N-nitrosodiethylamine and of fluorinated analogs in liver microsomal fractions.

In vitro metabolism of N-nitrosodiethylamine (NDEA) and of its two fluorinated analogs N-nitroso-2,2,2-trifluoroethyl-ethylamine (NDEA-F3) and N-nitroso-bis(2,2,2-trifluoro-ethyl)amine (NDEA-F6) was comparatively investigated using rat liver microsomes and S-9 fraction. Aldehydes, nitrite and unchanged nitrosamines were determined. Additionally the mutagenicity was measured in a Salmonella/mammalian microsome assay. NDEA and NDEA-F3 were deethylated and, to a smaller extent, denitrosated. Dealkylation of NDEA-F3 at the fluorinated ethyl group, however, was strongly inhibited. NDEA-F6 was practically not metabolized under the in vitro conditions used. In contrast to NDEA, the mutagenicity of NDEA-F3 was at best marginal; NDEA-F6 was not mutagenic. The results show that substitution of fluorine in beta-position of NDEA strongly influences alpha-C-hydroxylation and denitrosation.

Aldehydes↗
PubMed1982

Promoting effects of 3-amino-1,2,4-triazole on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine.

3-Amino-1,2,4-triazole (AT) promoted the development of thyroid tumors in rats treated with a subeffective dose of N-bis(2-hydroxypropyl)nitrosamine (DHPN) for thyroid tumorigenesis. The incidences of thyroid tumors at the end of the 20-week experiment were 91% in rats injected s.c. once a week for four weeks with 70 mg DHPN per 100 g body weight and then given diet containing 2000 p.p.m. AT for 12 weeks, 100% in rats injected s.c. once a week for eight weeks with 70 mg DHPN per 100 g body weight and then given diet containing 2000 p.p.m. AT for 12 weeks, and 58% in rats injected s.c. once a week for 8 weeks with 70 mg DHPN per 100 g body weight. Rats only injected s.c. once a week for four weeks with DHPN or only given diet containing AT for 12 weeks had no thyroid tumors at the end of the experiment.

Amitrole↗
PubMed1982

Mutagenicity and synthesis of alpha-substituted N-nitrosamines: derivatives with dithiocarbamic acid.

Disulfiram (DSF) can considerably alter the organotropy of chemical carcinogens. For N-nitrosodimethylamine and for N-nitrosodiethylamine the organotropy is shifted from the liver to the nasal cavity or the oesophagus, respectively. Whereas the influence of DSF or its metabolites on enzyme systems has been studied, little is known about its interaction with the carcinogens at a molecular level. Therefore, postulated reaction products of a series of alpha-hydroxylated N-nitroso-dialkylamines and dithiocarbamate were synthesized and tested for mutagenicity in Salmonella typhimurium TA 1535. The results show that the compounds conjugated at a primary alpha-C-atom are not mutagenic, whereas those conjugated at a secondary alpha-C-atom are active. The primary N-nitroso-dithiocarbamates represent unique examples of inactivated dialkyl-nitrosamine derivatives. In addition, their formation in vitro was indirectly demonstrated. The possible role these inactivated compounds may play during the DSF-modulation of carcinogenesis will be discussed.

Chemical Phenomena↗
PubMed1982

Fluoro-substituted N-nitrosamines. 3. Microsomal metabolism of N-nitrosodibutylamine and of fluorinated analogs.

In vitro metabolism of N-nitrosodibutylamine (NDBA) and of three fluorinated analogs, N-nitroso-4,4,4-trifluorobutyl-butylamine (NDBA-F3), N-nitroso-bis(4,4,4-trifluorobutyl)-amine (NDBA-F6) AND N-nitroso-bis(2,2,3,3,4,4,4-hepafluorobutyl)amine (NDBA-F14) was investigated with rat liver microsomes. To elucidate differences in metabolism caused by fluorination, aldehydes, nitrite and unchanged nitrosamines were determined. NDBA, NDBA--F3 and NDBA-F6 were dealkylated and to a smaller extent also denitrosated. Dealkylation at the fluorinated butyl groups was reduced in comparison to the unfluorinated butyl groups. NDBA-F14 was practically unmetabolized by microsomal enzymes in vitro.

Aldehydes↗
PubMed1982

Nitrosamine-induced pancreatic carcinogenesis in outbred and inbred Syrian hamsters.

Pancreatic carcinogenesis was investigated in outbred and in five strains of inbred Syrian golden hamsters utilizing the nitrosamines N-nitrosobis(2-hydroxypropyl)amine (BHP) and N-nitrosobis(2-oxopropyl)amine (BOP). Thirty eight outbred hamsters were treated for an average of 15 weeks with weekly s.c. inoculations of BHP at doses of 250,000 or 1000 mg/kg. Pancreatic carcinomas developed in 19%. Eighty nine inbred hamsters of strains CB, LHC and PD4 were given BHP at 250 mg/kg weekly for an average of 25 weeks. Pancreatic carcinomas developed in 61%. Pancreatic inflammation, fibrosis, and ductal hyperplasia were prominent. Toxic changes in the liver, biliary hyperplasia, and pulmonary interstitial inflammation were also prominent features of BHP-treated hamsters, along with occasional carcinomas of the liver and respiratory tract. One hundred and sixteen inbred hamsters of strains CB, LHC, LSH, MHA, and PD4 were treated with BOP at a dose of 5 mg/kg weekly for 15 weeks. The incidence of pancreatic carcinoma was 51%. BHP-treated hamsters exhibited pancreatic fibrosis and ductal hyperplasia. Livers of BHP-treated animals showed biliary hyperplasia, and lungs exhibited chronic inflammation. Occasional carcinomas of the liver and lung developed. From 243 hamsters treated with nitroso carcinogens, eight pancreatic ductal adenocarcinoma lines were derived that can be transplanted and propagated in inbred hamsters.

Adenocarcinoma↗