Formation of Nitrosamines in Food and in the Digestive System
John S. Wishnok Department of Nuhition and Food Sciences Massachusetts Institute of Technology Cambridge. 02139
N-nitrosodialkvlamines (nitrosamines) have been recognized since the mid 1950's as hepatotoxic agents (1-3) and have subsequently been found to be potent carcinogens in a wide variety of animal species (4.5). There is no direct evidence to associate human cancer with nitrosamines, hut every type of animal that has been tested has been found to be susceptible to nitrosamine carcinogenesis, and it is now widely accepted that nitrosamines are probably carcinogenic to humans (6). The carcinogenic potency of a given nitrosamine may vary among species (7) and between males and females of the same species (8).In addition, within a group of animals of the same strain and sex,the potency of nitrosamines can vary by several orders of magnitude (9,IO). For the BD rat (9) thisvariation can he roughly associated with molecular structure; the small, more volatile nitrosamines appear to be generally more active than the large, less volatile compounds (10). Most nitrosamines are liver carcinogens, but a number of them are highly specific carcinogens fo-r other organs (9,1 1 J . Table 1 lists the relative carrinorenicitv of some representntive nitrosamines, and Table 2 s h k some variations in organ specificity. The details of the biological interactions through which nitrosamines initiate tumors are unknown, but the most widely quoted hypotheses are generally based on the modification of intracellular DNA through alkylation of the DNA by an electrophilic metabolite of the nitrosamine (4,5,12-15). An example of such a sequence is shown in Figure 1. Nitrosamines have been mentioned as possible environmental carcinogens (6), and low levels of nitrosamines have been detected recently in the atmosphere in several areas (16, 17). N-nitrosodimethylamine, N-nitrosodiethylamine, and N-nitrosopyrrolidine (NP) have been found in a large number of cured meat products (see Table 3) (15). In addition to these s~ecificsituations, however, nitrosamines are somewhat atypical of environmental carcinogens in that they need not be explicitly present in the environment to be involved in carcinogenesis; this phenomenon is a direct conseauence of the chemistrv and biochemistry of their formation from secondary amines and nitrite salts. (There is evidence that nitrosamines can also he formed from primary (18) and tertiary (19) amines, but these situations have not been extensively investigated.)
Table 1.
Carcinoaenicitier of Ninwtnines
Nitroramina N-nitrosodimeth~lamine N-nitrolodiethylamine N-nitrorapyrroiidine N-nitroroproline N-nitroromorpnoline N-nitrorodiarnylamine N-nit~olodicyclohexylamine
Tabla 2P
"\ ,NNO R%H~
+
R
RCH
-
+
(R'CH,N~I
5
4
DNA
alkylatad DNA
+
