N-Nitrosopyrrolidine

N Nitrosopyrrolidine (formed when bacon that has been cured with sodium nitrite IS fned)... 

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

Co. and 20 mM nitrite in water, pH 3, 25 C, 60 min reaction], it was nitrosated to yield 3.62 mM 2,6-dimethyl-N-nitrosomorpho-line (DMNM), which was a 10% greater yield than that for a similar nitrosation of morpholine to give NMOR. This indicated a slightly larger rate constant for DMNM than for NMOR formation (3). Crude DMM is a 2 1 mixture of the cis and trans isomers ( 0). GC analysis of the product of the kinetic run showed that the 2 isomers were nitrosated at similar rates. Cis-DMNM [retention time (RT), 320 sec] was well separated from NMOR (RT, 430 sec), but trans-DMNM (RT, 405 sec) was not. Accordingly, we prepared pure cis-DMM, b.p. 133 C, by spinning-band fractional distillation of crude DMM and used it in the analytical procedure. The RT of N-nitrosopyrrolidine (NPYR) was 390 sec. 

We have previously shown in a survey on the occurence of volatile nitrosamines in commercial food of the German market that beer is the most important source of N-nitrosodimethylamine (NDMA) (Spiegelhalder et al, 1979 Preussmann et al., 1980 Spiegelhalder et al, 1980) The investigation of about 3000 food samples allowed the calculation of an average daily intake of 1.1 /ug NDMA and of 0.1-0.15/ig N-nitrosopyrrolidine (NPYR) for a male adult in the year 1978. For NDMA 64% (= 0.7yug/day) of the total daily intake resulted from the consumption of beer. 

Charcoal-cellulose acetate filter. N-nitrosodimethy1amine. %-nitrosoethylmethylamine. 8N-nitrosodiethylamine. N-nitrosopyrrolidine. 

Pyrrolidin-2-one is commonly found in coffee products in amounts in the mg/kg range.81 This has importance if coffee products come into contact with nitrites, because N-nitrosopyrrolidin-2-one is then produced, which can explain observed methylating activity.82... 

Two examples of synthesis of ant venom alkaloids via the Seebach (162) W-nitroso methodology have been published (163, 164). They start with N-nitrosopyrrolidine (125), which is sequentially alkylated at positions 2 and 5 (Schemes 14 and 15). 

An EPA method was created for measuring NDMA and six additional nitrosamines in drinking water (EPA Method 521) [55]. This method uses GC/ chemical ionization (CI)-MS/MS and enables the measurement of NDMA and six other nitrosamines (N-nitrosomethylethylamine, N-nitrosodiethylamine, N-nitroso-di-n-propylamine, N-nitroso-di- -butylamine, N-nitrosopyrrolidine, and N-nitrosopiperidine) in drinking water at detection limits ranging fi om 1.2 to 2.1 ng/L. A liquid chromatography (LC)/MS/MS method [56] can also be used to measure nine nitrosamines, including N-nitrosodiphenylamine, which is thermally unstable and cannot be measured using the EPA Method. 

N-nitroso compounds are widely recognized as being unquestionably nasty materials. More, than 100 of the 130 different N-nitroso compounds tested in animals have been shown to be carcinogenic (1). The site of the tumor depends upon the chemical structure of the N-nitroso compound, the route of administration and the species being tested. Three N-nitroso compounds, N-nitrosodimethylamine (NDMA), N-nitrosodi-ethylamine (NDEA) and N-nitrosopyrrolidine (NPYR), have been tested in dose response studies with rats between 1 and 5 parts per million (ppm) of these nitrosamines in the diet was found to produce a marginally significant number of tumors in a rat population of under 100 animals [2, 3, 4). 

N -nitrosonomicotine lB N-nitrosoproline P1NT107 N-nitrosopyrrolidine LB N-nitrososarcosine Pl TiOV N-N-octanoylnomicotine LB Non-3-en-8-one, 2-5-diepoxy-2(R)-hydroxy-5(R)-iso-propyl ... 

Several nitrosamines, including N-nitrosopyrrolidine (NP), N-nitrosodimethylamine (NDMA), and N-nitrosodiethylamine (NDEA), have been detected at various concentrations in this food. Table lists some typical values for the concentrations of these compounds in cooked bacon and some other prepared meat products (14). Nitrosopyrrolidine has been generally found, especially in bacon, at much higher levels than NDMA or NDEA, and most attention has consequently been directed toward this compound (15, 16). 

A dry 250-ml., one-necked, round-bottomed flask is equipped with a magnetic stirrer and a three-way stopcock. The flask is charged with 4 g. (0.053 mole) of ethyl nitrite (Note 1), 4 g. of dry tetrahydrofuran (Note 2), and 2.35 g. (0.033 mole) of pyrrolidine (Note 3) The stopcock is closed (Note 4), and the mixture is stirred at room temperature for 2 days Excess ethyl nitrite, tetrahydrofuran, and the ethanol formed are removed from the N-nitrosopyrrolidine (Note 5) by stirring at 25° under reduced pressure (10 mm., water aspirator, Note 6) for 2 hours. The stopcock is fitted with a rubber septum, the air in the system is replaced by dry argon (Notes 4 and 7), and 50 ml. of tetrahydrofuran is injected by syringe. A solution of lithium diisopropylamide is prepared in a separate dry 100-ml. flask by adding 21.1 ml (0 034 mole) of a 1.61 M solution of butyllithium in hexane (Note 8) to a solution of 4.76 ml. (0.034 mole) of diisopropylamine (Note 9) in 25 ml of tetrahydrofuran at -78° (dry ice-methanol bath) with... 

Nitrosamines are strong carcinogens2,3 N-nitrosopyrrolidine causes liver tumors in rats.2,4 Although the one-pot procedure described here prevents contact with the nitrosamine, utmost care must be used to avoid contact with the reaction mixture during all manipulations. 

Rangga-Tabbu C, Sleight SD. 1992. Development of preneoplastic lesions in the liver and nasal epithelium of rats initiated with N-nitrosodimethylamine or N-nitrosopyrrolidine and promoted with polybrominated biphenyls. Food Chem Toxicol 30( 11) 921 -926. 

Broadly, NOC are divided into two groups (a) /V-nitrosamines and (b) N-nitrosamides. In jV-nitrosamines, the two remaining substituent groups on the >N—N=0 atom can be either alkyl or aryl, or they can form the part of a heterocyclic ring (as in N-nitrosopyrrolidine). On the other hand, in N-nitrosamides, more correctly called N-acyl-N-nitroso compounds, one of these... 

The photochemistry of certain A-substituted heterocycles has also been studied. As part of a continuing investigation of the photolysis of A-nitroso compounds in solution, the conversion of A-nitroso-3-azabicyclo[3.2.2]nonane (65) into the oxime (66) by photolysis in the presence of acid was reported.58 N-Nitrosopyrrolidine is similarly transformed. The mechanism of this reaction is said58 to involve elimination of NOH with the formation of an imine as intermediate, and, in fact, in the photolysis of 2-ethyl-A-nitrosopiperidine (67), the tetrahydropyridine (68) is the major product. This mechanism certainly does not operate in the photolysis of iV-nitroso-2-azacyclo-octanone, which can be rationalized on the basis of an intramolecular hydrogen transfer [Eq. (16)].59 Acyclic iV-nitrosoamides behave in a similar fashion to IV-nitrosoamines.60... 

Mirvish (15) showed that weak bases are more easily N-nitrosated than strong bases under mildly acidic conditions. Since the secondary amine nitrogen on the 1,3-thiazolidine ring is much less basic (pKa 6.3) than in the pyrrolidine ring (pKfl 11.3), the formation of N-nitroso-l,3-thiazoline should be favorable and hence would be predicted to occur in products such as bacon where N nitrosopyrrolidine is of major concern. 

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