References pertinent to tobacco-specific A-nitrosamines

FIGURE XV-3 References pertinent to tobacco-specific A -nitrosamines, 1983 to 2004. 

In studies to elucidate the possible tumorigens in chewing tobacco and snuff, the only known components tumorigenic in laboratory animals identified were various NNAs, particularly the TSNAs NNN and NNK plus a group of A-nitrosamino acids, including NPRO. Whereas discussions and investigations on volatile NNAs [Druckrey and Preussmann (1057), Serfontein and Hurter (3595-3599)] and several TSNAs NNN, NAB [Boyland et al. (422, 423)] have appeared in the literature for over four decades, reports on identifications of A-nitrosamino acids are much more recent. 

Ohshima et al. (2852) identified several A-nitrosamino acids, 3-(methylnitrosamino)propanoic acid [also known as A-methyl-A-nitroso-P-alanine (NMPA)], 4-(methylnitrosamino) butanoic acid (NMBA), and l-nitroso-2-piperidinecarboxylic acid (also known as A-nitrosopipecolic acid), in various types of tobacco (cigarette, chewing, pipe, cigar, and snuff tobaccos). Decarboxylation of these A-nitrosamino acids would yield NEMA, A-nitrosomethylpropylamine, and NPIP. lARC (1986) did note the 1985 Ohshima et al. findings on these A-nitrosamino acids in tobacco. 

In studies with A-nitrosamino acid-spiked cigarettes, Brunnemann et al. (466) reported that added NMPA did not completely decarboxylate. Some was esterified to the methyl ester. Some of the intact acid, its methyl ester, and its decarboxylation product, NEMA, appeared in the MSS. Similar to NMBA, some NMBA transferred intact from the tobacco to the MSS, some formed the methyl ester, which appeared in the MSS, and some decarboxylated to yield A-nitrosomethylpropylamine, which also appeared in the MSS. NPRO primarily decarboxylated to NPYR. NSAR primarily decarboxylated to NDMA. 

Djordjevic et al. (1012) identified 4-(A-methylnitrosa-mino)-4-(3-pyridinyl)-l-butanoic acid (Ao-NNAC) in tobacco and in MSS. This acid was found only in the MSS from cigarettes containing tobacco spiked (2 mg/cigarette) with cotinine. From the results of in vitro nitrosation studies with radiolabeled cotinine and nicotine, Djordjevic et al. (995) proposed that the formation of 4-(A-methylnitrosamino)-4-(3-pyridinyl)-l-butanoic acid (Ao-NNAC) in tobacco proceeds via cotinine and its hydrolysis product 4-methyl-4-(3-pyridinyl)-l-butanoic acid rather than via nicotine. 

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