The formation of N-nitrosomethyl(2-oxopropyl)amine from N-nitrosobis(2-oxopropyl)amine in vivo

After injection of N-nitrosobis(2-oxopropyl)amine (BOP) (10mg/kg) to male Syrian golden hamsters there were higher concentrationsof BOP and many of its metabolites in the hamster pancreas comparedwith the liver and salivary gland. Also, a potential methylatingmetabolite of BOP, N-nitrosomethyl(2-oxopropyl)amine, was foundin both tissues.     

The production and repair of DNA damage by N-nitrosobis(2-oxopropyl)amine and azaserine in hamster and rat pancreas acinar and duct cells

The activation of N-nitrosobis(2-oxopropyl)amine (BOP) by pancreasacinar and duct tissue from Syrian hamsters and MRC-Wistar ratsin vitro and in vivo was measured in terms of the productionand repair of DNA damage. Hamsters were given BOP (1 x 10 mg/kg,s.c.). DNA single strand breaks (SSB) were measured over 2 weeks.Significantly more SSB were present in duct than in acinar tissue.Their persistence in the duct fragments was due to a slowerrate of repair. In a related experiment, duct fragments wereisolated from BOP treated (1 x 10 mg/kg, s.c.) hamsters 24 hafter exposure and cultured for 6 days, or were isolated 7 daysafter exposure. The extent of DNA damage was comparable in thetwo groups, indicating that the repair process(es) were stilloperative in cultured cells. Isolated duct fragments were exposedto either BOP or N-nitrosomethyl(2-oxopropyl)amine (MOP) invitro. MOP produced significantly more DNA damage than BOP evenat a 5-fold lower dose. This is consistent with the greatercarcinogenicity of MOP in the pancreas. BOP produced significantlyless DNA damage in the rat pancreas than in the hamster pancreas.The rate of repair was at least twice as fast in the rat pancreasas in the hamster pancreas. There did not appear to be any preferencefor acinar or duct tissue in rats as there was lit hamsters.This procedure was validated in rats by the use of the rat pancreascarcinogen azaserine, which only produced DNA damage in ratacinar tissue.     

Cholecystokinin inhibits DNA alkylation induced by N-nitrosobis (2-oxopropyl)amine (BOP) in hamster pancreas.

Cholecystokinin (CCK) inhibits pancreatic cancer but not hepatic tumor induction by N-nitrosobis (2-oxopropyl) amine (BOP) in hamsters when administered with or shortly before BOP. In this study, we evaluated the capability of sulfated CCK-8 to inhibit DNA alkylation in the hamster pancreas. We examined the pattern of O6-methylguanine (G6-Me) and N7-methylguanine (G7-Me) in pancreatic ductal, acinar and liver tissues from Syrian hamsters treated with a single dose of BOP (20 mg/kg s.c.) and with five s.c. injections of CCK-8 (200 pM/kg, 30 min apart). The first CCK injection was given either 90 min before, or together, or 3 h after POP administration. The amount of G6-Me in liver DNA did not differ significantly. We observed a decrease of G7-Me in the liver of the group treated with CCK together with POP as compared to POP alone (P less than 0.005). Lower amounts of G6-Me were found in ductal preparations (P less than 0.01) of the animals treated with CCK before POP as compared to POP alone. CCK also modified the pattern of alkylation in the acinar tissue, but without a clear relationship with the timing of administration. The results suggest that the inhibitory effect of CCK-8 on pancreatic carcinogenicity of BOP could be related to its capability to modify DNA alkylation by yet unknown mechanisms.     

Nicotinamide and selenium stimulate the repair of DNA damage produced by N-nitrosobis (2-oxopropyl) amine

The effects of nicotinamide (NIC) and selenium (SE), given alone or together, on N-nitrosobis (2-oxopropyl) amine (BOP)-induced DNA damage were measured in rat liver and colon. SE stimulated DNA repair in both tissues, whereas NIC was without effect. The failure of NIC to stimulate the repair of BOP-induced DNA damage in rat liver, where BOP is a methylating and hydroxypropylating agent, suggested that the nature of the DNA damaging agent could be important. NIC stimulated the repair of DNA damage induced by BOP (methylating agent in the pancreas) and N-nitrosodiethylamine (ethylating agent) but not by azaserine (carboxymethylating agent) or N-nitroso-5,6-dihydrouracil (carboxyethylating agent).     

Species specificity in the metabolism of N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine to mutagens by isolated rat and hamster hepatocytes

The metabolic activation of the carcinogens N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) by Fischer rat and Syrian hamster hepatocytes was investigated in order to determine the existence of species differences in the induction of cell mutation. The conversion of BOP and HPOP into forms mutagenic to V79 cells was studied by using the hepatocyte-mediated mutagenicity assay. Mutations at the hypoxanthine:guanine phosphoribosyltransferase locus and the Na-K-ATPase locus were scored by the induction of 6-thioguanine resistance (TGr) or ouabain resistance (Ouar), respectively. Hepatocytes of both species were capable of converting BOP and HPOP to mutagens for V79 cells in a dose-dependent manner. Metabolism of BOP by rat hepatocytes resulted in higher mutation frequencies than that by hamster hepatocytes. At a BOP concentration of 240 microM, rat hepatocyte metabolism yielded 90.7 TGr mutants and 19.5 Ouar mutants per 10(5) V79 cells. At the same concentration, hamster hepatocyte metabolism of BOP yielded 54.1 TGr mutants and 13.0 Ouar mutants per 10(5) V79 cells. These results did not correlate with the known carcinogenic potency of BOP in the hamster as compared to the rat. Hamster hepatocytes carried out the catabolism of BOP to CO2 at faster rates than rat hepatocytes; therefore, the species difference in mutagenic activation was not due to a defect in BOP uptake or metabolism by hamster hepatocytes. In contrast, metabolism of HPOP by hamster hepatocytes resulted in significantly higher mutation frequencies than that by rat hepatocytes. At an HPOP concentration of 240 microM, hamster hepatocyte metabolism yielded 83.5 TGr mutants per 10(5) V79 cells; rat hepatocyte metabolism yielded only 19.8 TGr mutants per 10(5) V79 cells. This species difference in mutagenic activation correlated well with the known potency of HPOP as a carcinogen for the hamster as compared to the rat. Since hamster pancreatic cells and subcellular fractions are known to have very limited capacity to perform the metabolic activation of HPOP, the results of this study imply that liver metabolism plays an important role in the conversion of HPOP to an agent(s) which subsequently affects the hamster pancreas. The mutagenic potency of BOP versus HPOP was compared after metabolism by hepatocytes from both species. Following their metabolism by hamster hepatocytes, the two compounds were nearly equivalent in mutagenic potency. After metabolism by rat hepatocytes, BOP was significantly more potent mutagen than HPOP.(ABSTRACT TRUNCATED AT 400 WORDS)     

Induction of pancreatic DNA damage and nodules in rats treated with N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine

DNA damage was demonstrated by alkaline elution analysis inpancreas of rats treated with 100 mg/kg N-nitrosobis(2-oxopropyl)amine(BOP) and 20 mg/kg N-nitroso(2-hydroxy-propyl)2-oxopropyl)amine(HPOP). Young rats were treated with a single dose of BOP orHPOP and autopsied 4 months later. Histologically the pancreasescontained multiple foci and nodules of atypical acinar cellswhich were not seen in controls.     

Comparative carcinogenicity of N-nitrosobis(2-oxopropyl)-amine and N-nitrosomethyl(2-oxopropyl)amine following subcutaneous or oral administration to rats

The carcinogenicity of N-nitrosomethyl(2-oxopropyl)amine (MOP), a postulated proximate carcinogen of N-nitrosobis(2-oxopropyl)-amine (BOP), was tested after either a single subcutaneous (s.c.) injection or weekly intragastric (i.g.) administration in Wistar-derived MRC rats and was compared with the effect of BOP, given similarly and at equitoxic doses. Following i.g. administration, MOP induced a high incidence of neoplasms in the pharynx and esophagus which, however, were not affected by BOP; on the other hand, tumors of the thyroid, lungs, colon and urethra occurred in a greater incidence following BOP than after MOP, and renal neoplasms were found only following MOP, given s.c. Moreover, there were remarkable sex differences in the responses of the rats' respiratory and urothelial tissues to these two carcinogens: nasal cavity carcinomas, pulmonary adenomas, urinary and urethra papillomas were induced primarily or exclusively in male rats treated with BOP, either s.c. or i.g., whereas such sex differences were not found following either route of MOP administration. There were also differences in the spectrum of the neoplasms induced by BOP or MOP depending upon the route of their administration. For example, MOP was more effective in inducing nasal, esophageal and hepatic tumors when given orally, compared to its effect following the s.c. route, and thyroid and renal tumors were induced only after its s.c. injection. The results point to a complexity of nitrosamine carcinogenesis and also indicate that in some tissues activation of BOP, but not of MOP, depends on sex hormones.     

Sex differences in the single-dose toxicokinetics of N-nitrosomethyl(2-hydroxyethyl)amine in the rat

The single-dose toxicokinetics of N-nitrosomethyl(2-hydroxyethyl)amine (NMHA) has been characterized in 8-week-old Fischer 344 rats by analysis using high-performance liquid chromatography of serial blood samples. An i.v. bolus dose of 0.6 mumol/kg to male rats revealed biphasic first-order elimination with a terminal half-life of 37.4 +/- 1.7 min for unchanged NMHA and 101 +/- 6 min for total radioactivity, and extensive conversion to polar metabolites was seen in the high-performance liquid chromatographic assays. The systemic blood clearance and apparent steady-state volume of distribution for unchanged NMHA were 13.1 +/- 0.9 ml/min/kg, and 685 +/- 31 ml/kg, respectively. Renal blood clearance and intrinsic hepatic clearance were estimated to be 0.805 +/- 0.024 and 16.7 +/- 2.1 ml/min/kg, respectively. A similar dose given to female rats yielded a terminal half-life for NMHA of 27.2 +/- 1.2 min, a steady-state volume of distribution of 652 +/- 23 ml/kg, and systemic blood, renal blood, and intrinsic hepatic clearances of 16.9 +/- 1.3, 1.45 +/- 0.14, and 22.5 +/- 0.3 ml/min/kg, respectively. The sex differences in terminal half-life and systemic blood, renal blood, and intrinsic hepatic clearances were significant at the P less than 0.05 level. Larger doses given by gavage, which appeared to be completely absorbed from the gut, indicated systemic bioavailabilities for unchanged NMHA of 78 +/- 10% and 69 +/- 1% for male and female rats, respectively. Binding of NMHA to plasma proteins was found to be negligible. Taken together the data allow for the conclusion that the observed sex differences in toxicokinetic parameters are due to differences in the intrinsic hepatic clearance of the compound. This difference in the ability of the liver to metabolize NMHA in vivo correlates with and may contribute to the greater susceptibility of female rats to hepatocarcinogenesis and of male rats to development of tumors in the nasal epithelium following oral exposure to NMHA.     

Carcinogenicity of N-nitrosomethyl(2-oxobutyl)amine and N-nitrosomethyl-(3-oxobutyl)amine in Syrian hamsters with special reference to the pancreas

Studies with oxidized derivatives of N-nitrosodi-n-propylamine suggested a structure-activity relationship between pancreatic cancer induction in Syrian hamsters and position and degree of nitrosamine oxidation. To elucidate the importance of the position of the oxidized substituent relative to the N-nitroso group in pancreatic carcinogenesis, we compared the toxicity and carcinogenicity of two substituted methylbutylnitrosamines. N-Nitrosomethyl(2-oxobutyl)amine (M-2-OB) and N-nitrosomethyl(3-oxobutyl)amine (M-3-OB) were given in equitoxic doses to male and female Syrian hamsters. The 50% lethal doses for M-2-OB and M-3-OB in males and females, respectively, were 92 and 160 and 705 and 810 mg/kg body weight. M-2-OB, although given in significantly smaller doses (minimum dose, 2.3 mg/kg body weight) than was M-3-OB (minimum dose, 17.6 mg/kg body weight), induced a much broader spectrum of neoplasms (in 17 tissues), whereas M-3-OB induced tumors in only 5 tissues and had no carcinogenic effect in the pancreas. M-2-OB, however, produced pancreatic ductular-ductal adenocarcinomas in over 90% of the males and 67% of the females, even at the lowest doses (2.3 and 4.0 mg/kg, respectively). Although both compounds caused a similar incidence of morphologically equivalent neoplasms (mostly adenocarcinomas) in the nasal and paranasal cavities, the remaining distribution of affected tissues differed significantly. M-2-OB predominantly affected the lip (epitheliomas, squamous cell carcinomas), liver (cholangiomas and cholangiocarcinomas), and flank organ (epitheliomas, squamous cell carcinomas). The principal target organs for M-3-OB were the cheek pouch (papillomas, squamous cell carcinomas) and trachea (polyps). In contrast to M-2-OB, M-3-OB did not induce renal and urethral tumors. These findings indicate the importance of the 2-oxo group as a prerequisite for the carcinogenicity of methylalkylnitrosamines in the hamster pancreas; however, a methyl group in one aliphatic chain, alpha to the N-nitroso function, appears to cause the molecule to lose its selectivity for the pancreas.     

DNA Alkylation by Nitrosobis-(2-oxopropyl) amine in Rats of Different Ages

We have examined the methylation of liver DNA (O⁶- and N⁷-methylguanine) by nitrosobis-(2-oxopropyl)amine (BOP) in male and female rats at various ages, following treatment with 2.5 mg of BOP; this dose given twice weekly for 30 weeks induces tumors in all animals. Except in young rats there was more methylation in female rat liver than in male rat liver, when adjusted for different sizes of the animals. There were differences in the extent of methylation between young (4 weeks) and older rats, but not between young adult (20 weeks) and old adult (65 weeks) males; the latter developed liver tumors when treated with BOP, and the former did not. There was no obvious relation between increased susceptibility to liver tumor induction by BOP and the extent of alkylation of liver DNA. Methylation of DNA was lower in the kidney than in the liver and, here, there was little difference between the sexes. In the testis there was N⁷-methylation of guanine in DNA, but no O⁶-methylguanine was detected.     

DNA alkylation by nitrosobis-(2-oxopropyl)amine in rats of different ages

We have examined the methylation of liver DNA (O6- and N7-methylguanine) by nitrosobis-(2-oxopropyl)amine (BOP) in male and female rats at various ages, following treatment with 2.5 mg of BOP; this dose given twice weekly for 30 weeks induces tumors in all animals. Except in young rats there was more methylation in female rat liver than in male rat liver, when adjusted for different sizes of the animals. There were differences in the extent of methylation between young (4 weeks) and older rats, but not between young adult (20 weeks) and old adult (65 weeks) males; the latter developed liver tumors when treated with BOP, and the former did not. There was no obvious relation between increased susceptibility to liver tumor induction by BOP and the extent of alkylation of liver DNA. Methylation of DNA was lower in the kidney than in the liver and, here, there was little difference between the sexes. In the testis there was N7-methylation of guanine in DNA, but no O6-methylguanine was detected.     

Inhibitory effect of selenium on hamster pancreatic cancer induction by N'-nitrosobis(2-oxopropyl)amine

The effect of selenium intake on the development of pancreatic cancer was investigated in female Syrian golden hamsters. Four-week-old hamsters were divided into 2 groups according to the selenium level in their drinking water and were fed a purified diet containing less than 0.05 ppm selenium. Starting 4 weeks later, groups received 10 s.c. injections at weekly intervals of N'-nitrosobis(2-oxopropyl)amine (BOP) dissolved in saline, while controls received saline alone. When the animals were killed 18 weeks after the last injection, palpable tumors were less frequent in the high-selenium group than in animals receiving low-selenium supplement, the numbers of histologically diagnosed cancerous lesions also being significantly reduced by high selenium intake. The selenium level and glutathione peroxidase activity in serum and pancreas were significantly greater in the high-selenium group. Moreover, selenium levels and glutathione peroxidase activity were both significantly higher in tumor-bearing tissue. The results suggest that glutathione peroxidase is involved as an intermediate factor in prevention of carcinogenesis by selenium.     

Uptake of N-nitrosobis(2-oxopropyl)amine by isolated rat and hamster hepatocytes: species differences and evidence for an active carrier-mediated transport process

The rates of uptake of the carcinogen N-nitrosobis(2-oxo-propyl)amine(BOP) by hepatocytes isolated from Fischer rats and Syrian hamsterswere determined in order to investigate species differencesin cellular transport of the carcinogen. Initial rates of uptakeof (1-¹⁴C)BOP by hepatocytes were measured using a rapid centrifugationtechnique. At cell densities from 1.5 to 6 x 10⁶ cells/ml, initialrates of uptake were as much as 4-fold more rapid in hamsterhepatocytes than in those of the rat. The cell/medium distributionratio for hamster hepatocytes reached a value of 9.0 after a20-min incubation with an extracellular BOP concentration of20 µM. Under the same conditions, the cell/medium distributionratio for rat hepatocytes was only 2.4. These results indicatedthat BOP uptake proceeded against a concentration gradient andwas more rapid in hamster hepatocytes. In both species, therates of uptake were saturable with increasing concentration(2–685 µM) and displayed biphasic kinetics characteristicof high-affinity (Km < 20 µM) and low-affinity (Km30 µM) process for the uptake of BOP. Evidence for theinvolvement of an ATP-dependent active carrier-mediated transportprocess was obtained from experiments in which hepatocytes werepreincubated with metabolic inhibitors. Significant inhibitionof uptake was observed in the presence of KCN, carbonyl cyanide-3-chlorophenylhydrazone,antimucin A, oligomycin and other agents which interfere withelectron transport or ATP generation. Based on the reductionin uptake rates, rat hepatocytes were more sensitive to theeffects of these inhibitors. These results suggest that theentry of BOP into hepatocytes is under cellular regulation andthat the more rapid rate of uptake in liver cells of the hamstermay be one factor responsible for the observation that BOP isa more potent hepatotoxin and carcinogen in this species.     

Fibrin deposition in autochthonous Syrian hamster pancreatic adenocarcinomas induced by the chemical carcinogen N-nitroso-bis(2-oxopropyl)amine

Immunofluorescence studies have demonstrated the presence of fib (a group of fibrinogen- and fibrin-related proteins that react with antibodies raised against fibrinogen) in the stroma of several transplantable animal and autochthonous human tumors. Acceptance of these reports was tempered by the possibility of artifactual clotting and fibrinolysis associated with tumor removal or tumor transplantation and by the relatively poor histology inevitable when immunofluorescence is performed on frozen tissue sections. An immunoperoxidase study therefore was undertaken of the ductal pancreatic carcinomas induced in female LGV Syrian hamsters by N-nitroso-bis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4]. Artifactual clotting and fibrinolysis associated with tumor removal were avoided by systemic anticoagulation and antifibrinolysis. Fibronectin and residual fib were prominent components of tumor stroma. Prominent fib deposits also were found in a new location: the basement membrane zones of atypical pancreatic ducts and invasive carcinomas. In contrast, fib deposits were never found in the basement membranes of blood vessels, nerves, or pancreatic acini of BOP-treated or normal animals, or in the ductal basement membranes in the normal pancreas. Ducts with marked atypicality and invasive pancreatic carcinomas frequently exhibited discontinuous basement membrane staining for fib, which often paralleled loss of staining for the integral basement membrane proteins--type IV collagen and laminin. Loss of acquired fib basement membrane staining with malignant disease progression may serve as a new marker for local tumor invasion.     

Beta-oxidized N-nitrosoalkylcarbamates as models for DNA alkylation by N-nitrosobis(2-oxopropyl)amine in Syrian hamsters

A single dose of N-nitrosobis(2-oxopropyl)amine (NDOPA) can selectively induce pancreatic-duct adenocarcinomas in Syrian hamsters. Multiple doses or a higher single dose can induce tumours of the liver and other organs. Our earlier studies employing NDOPA systematically labelled with 14C in the three-carbon chain showed that hamster pancreatic DNA is almost exclusively methylated and that the sole source of the methyl group is the alpha carbon of NDOPA. Hamster liver DNA was equally methylated and alkylated by a three-carbon chain. Current studies using generally labelled tritiated NDOPA with a very high specific activity have shown that the three-carbon alkylation is 2-hydroxypropylation. We have identified two adducts isolated from hamster liver DNA, N7-(2-hydroxypropyl)-guanine and O6-(2-hydroxypropyl)guanine, which contain this group, and we have also isolated and identified N7-methylguanine and O6-methylguanine in DNA from hamster liver and pancreas. beta-Oxidized N-nitrosocarbamates, ethyl N-nitroso-2-oxopropylcarbamate (NOPC) and ethyl N-nitroso-2-hydroxypropylcarbamate (NHPC), are useful models for predicting the DNA adducts observed in vivo following NDOPA treatment. Base-catalysed decomposition of NOPC in the presence of exogenous DNA yields five methylated purines (N3-, N7- and O6-methylguanines and N1- and N3-methyladenines). NHPC, a model for N-nitrosamines containing the 2-hydroxypropyl group, reacts with guanosine to yield N7- and O6-(2-hydroxypropyl)guanines.(ABSTRACT TRUNCATED AT 250 WORDS)     

Common metabolites of N-nitroso-2,6-dimethylomorpholine and N-nitroso-bis(2-oxopropyl)amine in the Syrian hamster.

N-Nitroso-2,6-demethylmorpholine (NDMM) administered intraperitoneally to Syrian hamsters was metabolized to N-nitroso-bis(2-hydroxypropy)(2-oxopropyl)amine(HPOP) and N-nitroso-bis(2-hydroxpropyl)amine (BHP) which were identified in blood and urine. The potent pancreatic carcinogen N-nitroso-bis(2-oxoproply)amine was previously shown to form the same metabolites. Preliminary results indicate that NDMM also induces pancreatic and other tumors in Syrian hamsters, similar to those found following BHP treatment.     

Metabolism of the Z and E isomers of N-nitroso-N-methyl-(2-oxopropyl)amine by rat hepatocytes

The metabolism of N-nitroso-N-methyl-N-(2-oxopropyl)amine was examined using freshly isolated hepatocytes from Fischer 344 rats. As determined by high performance liquid chromatography, it was found that the E isomer was preferentially metabolized when the parent mixture was used. When the two isomers were studied separately, the E isomer was efficiently metabolized in the hepatocytic system, whereas the Z isomer was not. The kinetics of disappearance of the Z isomer during metabolism was identical to that for the reequilibration of the Z isomer to the mixture of isomers in the absence of a metabolizing system.     

Inhibitory effect of dibutyltin dichloride on pancreatic adenocarcinoma development by N-nitrosobis(2-oxopropyl)amine in the Syrian hamster

The effects of a single intragastric application of dibutyltin dichloride (DT), at a dose of 30 mg/kg body weight, on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic carcinogenesis were studied in female Syrian golden hamsters. DT, which has been shown to selectively induce bile duct injury, was administered either 1 week before or after BOP initiation. BOP was injected subcutaneously once a week for 5 weeks at a dose of 10 mg/kg body weight. Controls were injected with BOP alone or given DT without carcinogen. Animals sacrificed at the end of the 25-week experimental period showed a significant inhibitory effect of DT on pancreatic carcinoma induction when DT was given before BOP treatment, although no such influence was evident with DT treatment following BOP exposure. These results indicate that the bile duct and more especially common bile-duct injury induced by DT may be relevant to the inhibition of the initiation stage of BOP-induced pancreatic carcinoma development in Syrian hamsters.     

Carcinogenicity of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, N-nitrosobis(2-hydroxypropyl)amine and cis-N-nitroso-2,6-dimethylmorpholine administered continuously in the Syrian hamster, and the effect of dietary protein on N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine carcinogenesis

The effect of continuous week-long administration of the threepancreatic carcinogens N-nitroso(2-hydroxypropyl)(2-oxo-propyl)amine(HPOP), N-mtrosobis(2-hydroxypropyl)amine (BHP), and cis-N-nitroso-2,6-dimethylmorpholine(cis-NNDM), by a s.c. implanted osmotic pump, was examined inSyrian hamsters. HPOP at total doses of 220–250 mg/kgbody weight induced ductal adenocarcinomas in the pancreas (41%),and cholangiomas (18%) and cholangiocarcinomas (18%) in theliver, 25 weeks following the initiation of treatment. Higherdoses of HPOP resulted in severe hepatic injury and increasedmortality (LD₅₀=280 mg/kg). Cis-NNDM and BHP were less toxicthan HPOP and induced pancreatic lesions at doses of 950 mg/kg.These data document that a week-long schedule of continuousadministration of HPOP for the induction of pancreatic cancercompares favorably with those involving weekly injections. Applicationof this model to study the effect of dietary protein in HPOP-inducedcarcinogenicity showed that the number of cystic, intermediateand tubular complexes in the pancreas was significantly higherin animals fed a 20% as compared to an 8% protein diet 2 weeksprior to HPOP administration. Furthermore, the incidence ofpancreatic adenocarcinomas and in situ carcinomas was only 13%in the hamsters fed the low-protein diet as compared to 46%in those fed the high-protein diet.     

Pancreatic carcinogenic effect of N-nitrosobis (2-oxobutyl)_amine and N-nitroso (2-oxobutyl) (2-oxopropyl)amine in Syrian hamster

A single subcutaneous injection of N-nitrosobis(2-oxobuty)amine (BOB) and N-nitroso(2-oxobutyl)(2-oxopropyl)amine (OBOB) induced a high incidence of pancreatic ductular neoplasms in Syrian hamsters. Both compounds showed a cytotoxic effect on pancreatic islet cells in toxic doses. Since both compounds, like N-nitroso(2-hydroxypropyl) (2-oxopropyl)amine (HPOP), can form cyclic structures resembling the hexose sugars and the glucose-moiety of the streptozotocin, it can be assumed that the ability of these 2 carcinogens to cyclize is important in their affinity for the pancreas. However, OBOP had a greater pancreatic carcinogenic effect than BOB, the primary target tissue of which was the liver. Hence factors other than cyclization, such as the presence of the 2-oxo group in the aliphatic chains, also appear to be important for the pancreatic carcinogenicity of this class of nitrosamines.