Nitrosamine carcinogenesis

GUO Z, SMITH T J, WANG E, SADRIEH N, MA Q, THOMAS P E and YANG C S (1992) Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabohzing enzymes and nitrosamine metabolism in rats . Carcinogenesis, 13 2205-10. 

The first ten years of nitrosamine research, particularly with respect to carcinogenesis, were summarized in an admirable review by Magee and Barnes (J ). Since that time an enormous amount of work has been carried out on those substances. Some of this work up to 1974 was reviewed by Magee, Montesano and Preussmann (4. Recently, Lai and Arcos ( 5 provided a useful synopsis of contemporary work on the bioactivation of some selected dialkyInitrosamines. 

These studies on NPYR are typical of the state of the art in cyclic nitrosamine metabolism ai d activation. The major metabolic pathways have been rather well characterized, but data on the relationship of these pathways to carcinogenesis are limited. This is especially true of the organospecific effects of NPYR and the other cyclic nitrosamines. For example, the main target organs for NPYR in the Syrian golden hamster are the trachea and nasal cavity rather than the liver. This is in spite... 

Our studies on cyclic nitrosamine metabolism are supported by NCI Grants CA-21393, CA23901, and CA12376. This is paper Number 34 in A Study of Chemical Carcinogenesis. ... 

It does suggest, however, that our original assumptions concerning d were at least reasonable. In addition, the dose-depen-dent model can be manipulated to examine - in a general sense -some aspects of interspecies variations in susceptibility to nitrosamine carcinogenesis. 

The experiments with deuterium-labeled nitrosamines illustrate two important points. One is that oxidation of nitrosamines takes place at more than one position in the molecule, and the outcome of the balance of such competing reactions probably is the determinant of carcinogenic potency. The second is that the reason for the failure of carcinogenesis to be mirrored in many cases by the microsomally activated bacterial mutagenicity is that there can be several metabolic steps leading to formation of the proximate carcinogenic agent and not all of these need necessarily involve microsomal enzymes. ... 

Mirvish (53,54) discovered that vitamin C could inhibit ni-trosation reactions. The purely chemical interaction of ascorbic acid with nitrite has been studied for theoretical reasons and because of its importance in the preservation of foods. This interaction has received increased attention for minimizing the presence of nitrosamines and nitrosamides in the environment, and especially in foods. We have studied the relationship in gastric carcinogenesis between high levels of nitrite, including pickling, and of vitamin C as a protective and inhibiting element. 

Chung, F.L. and Xu, Y. (1992). Increased 8-oxodeoxyguanosine levels in lung DNA of A/J mice and F344 rats treated with the tobacco-specific nitrosamine 4-(methyl-nitrosamine)-l-(3-pyridyl)-l-butanone. Carcinogenesis 13, 1269-1272. 

The a-carbons of nitrosamines undergo enzymatic hydroxylation followed by oxidative cleavage leading to the formation of alkyldiazo hydroxides, alkyldiazonium ions and alkyl cations [34]. These cations are postulated to initiate the process of carcinogenesis in some cases by alkylating the base units of DNA [35, 36]. 

A tribute to Ernst L. Wynder. Chem Res Toxicol 14 767-790 Idris AM, Nair J, Oshima H, Friesen M, Bronet I, Faustman EM, Bartsch H (1991) Unusually high levels of carcinogenic tobacco-specific nitrosamines in Sudan snuff (toombak). Carcinogenesis 12 1115-1118... 

Tatematsu M, Miyata Y, Mizutani M, et al. 1977. [Summation effect of N-butyl-n(4-hydroxybutyl)nitrosamine,N-(4-(5-nitro-2-furyl)-2thiazoly) formamide, N-2-fluoroenylacetanide, and 3,3 -dichlorobenzidine on urinary bladder carcinogenesis in rats.] Jarm 68 193-202. (Japanese)... 

Lijinsky W, Reuber MD Comparative carcinogenesis by some aliphatic nitrosamines in Fischer rats. Cancer Lett 14 297-302, 1981... 

NT087 Hoffmann, D., M. V. Djordjevic, A. Rivenson, E. Zang, D. Desai, and S. Amin. A study of tobacco carcinogenesis. LI. Relative potencies of tobacco-specific N-nitrosamines as inducers of lung tumours in A/J mice. Cancer Lett 1993 71(1-3) 25-30. 

Amin, and R. Hoffmann. A study of tobacco carcinogenesis XLIV. Bioassay in A/] mice of some N-nitrosamines. Cancer Lett 1989 47(1-2) 111-114. 

Desai, and S. S. Hecht. Evidence for endogenous formation of tobacco—specific nitrosamines in rats treated with tobacco alkaloids and sodium nitrite. Carcinogenesis 1997 18(3) 587—592. NT257 Mendez-Alvarez, E., R. Soto-Otero, I. Sanchez-Sellero, and M. Lopez-Ri-vadulla Lamas. Inhibition of brain monoamine oxidase by adducts of 1, 2,3,4-tetrahydroisoquinoline with components of cigarette smoke. Life Sci 1997 60(19) 1719-1727. 

In conclusion, we demonstrate by this preliminary review of our work that the base-catalyzed fragmentation of B-hydroxynitro-samines is a general transformation. The rate of the transformation is a significant function of structure as well as the catalyst and the conditions. Several other base-catalyzed transformations of nitrosamines have been observed and all of these reactions are expected to be of significance in the area of nitrosamine carcinogenesis. 

Quantitative Aspects of Exposure and Mechanism in A Nitrosamine Carcinogenesis... 

N-nitrosodialkylamines - nitrosamines - constitute one of the most extensive series of known chemical carcinogens. Most nitrosamines can initiate tumors in at least one animal species, and all animal species which have so far been tested are susceptible to nitrosamine carcinogenesis O, 2 ). 

In addition to these potentially important epidemiological aspects, the nitrosamines are especially interesting in terms of the biochemistry of chemical carcinogenesis. This is exemplified most strikingly, perhaps, in the organ specificity of these compounds (], 11), and in the wide variations in potency within the series (10, 12). 

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