Nitrosopyrrolidines

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),... 

Evidence exists that the relative solubility of amines and inhibitors in heterogeneous oil-water systems could be decisive in formation of nitrosamines and blocking these reactions, Nitrosopyrrolidine formation in bacon predominates in the adipose tissue despite the fact that its precursor, proline, predominates in the lean tissue (5,6,7). Mottram and Patterson (8) partly attribute this phenomenon to the fact that the adipose tissue furnishes a medium in which nitrosation is favored, Massey, et al, (9) found that the presence of decane in a model heterogeneous system caused a 20-fold increase in rate of nitrosamine formation from lipophilic dihexylamine, but had no effect on nitrosation of hydrophilic pyrrolidine. Ascorbic acid in the presence of decane enhanced the synthesis of nitrosamines from lipophilic amines, but had no effect on nitrosation of pyrrolidine. The oil-soluble inhibitor ascorbyl palmitate had little influence on the formation of nitrosamines in the presence or absence of decane. 

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. 

Table I lists the concentrations of nitrosodimethylamine (NDMA) and nitrosodiethylamine (NDEA) in some of the tobacco products which had greater than 0.5% nitrate content. Tobacco with less than 0.5% nitrate content, such as Bright tobaccos, yielded NDMA, NDEA and nitrosopyrrolidine (NPYR) generally below 5 ppb. The relatively high concentrations of NDMA in fine cut tobaccos and in snuff are possibly of significance in the increased risk for oral cancer among snuff dippers who use these tobacco types repeatedly each day by placing a pinch of the product directly into the gingival buccal fold (6,7).

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). 

TABLE 27. A comparison of selected torsional angles (degrees) of 3-phenyl-A-nitrosopyrrolidine, 81, as calculated by MM2 and measured by X-ray crystallography"... 

FIGURE 12. Electronic circular dichroism spectra of (S)-3-methyl-lV-nitrosopyrrolidine [(S)-147]. Reproduced from Reference 133 by permission of Acta Chemica Scandinavica... 

The extent of formation of these NOC depends upon the presence of nitrogen oxides present in the atmosphere during the manufacturing cycle. The major contaminants are NDMA, A-nitrosodiethylamine (NDEA), A-nitrosopyrrolidine (NPYR), NMOR, A-nitrosodiphenylamine (NDPhA), A-nitrosopiperidine (NPIP) and A-nitrosodibutylamine (NDBA)68. NMOR was found in the hot process areas NDMA occurred in tube production areas in which NDPhA was being used as retarder and tetramethylthiuram disulphide as an accelerator. Figure 12 shows a proposed reaction scheme of formation of NOC in the rubber industry and subsequent exposure67. 

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). 

---